Combination therapies with disulfiram

ABSTRACT

Disclosed herein are compositions and methods for increasing lifespan, for preventing or treating a disease including an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system in a mammal. Also disclosed herein are compositions and methods for improving effectiveness of a vaccine in a mammal. The compositions comprise, at least, a therapeutically effective amount of disulfiram and one or more additional ingredients.

CROSS-REFERENCE

This application claims priority to U.S. Provisional Application No. 63/080,639 filed Sep. 18, 2020, the contents of which is incorporated by reference herein in its entirety.

BACKGROUND

Of the approximately 150,000 human deaths per day, approximately two-thirds are due to age-related causes. Aging leads to functional deterioration and progressive decline across multiple tissues, organs, and systems, including the immune system, that arise from the progressive accumulation of cellular and tissue damage. This damage may be attributed, in part, to dysfunction or disruption in one or more signaling pathways. Accordingly, there remains an unmet need for compositions and methods that stop, slow, or reverse these dysfunctions or disruptions and are capable of thereby treating aging-related disorders and/or reducing symptoms of aging.

SUMMARY

The present invention addresses this need. Accordingly, the present disclosure relates to compositions and methods for increasing lifespan, for preventing or treating a disease including an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system in a mammal. The present disclosure additionally relates to compositions and methods for improving effectiveness of a vaccine in a mammal.

An aspect of the present disclosure is a method for inhibiting and/or reducing pyroptotic cell death in a cell. The method comprises contacting the cell with an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde, thereby inhibiting and/or reducing pyroptotic cell death.

In some embodiments, the disulfiram and cinnamaldehyde are included in one composition and the composition consists essentially of disulfiram and cinnamaldehyde. In some cases, the composition further comprises one or more additional ingredients from Table 1.

In various embodiments, the method comprises contacting the cell with a first composition consisting essentially of disulfiram and contacting the cell with a second composition consisting essentially cinnamaldehyde. In some cases, the either or both of the first composition and the second composition further comprises one or more additional ingredients from Table 1.

In embodiments, inhibiting and/or reducing pyroptotic cell death in the cell increases the lifespan of the cell.

In some embodiments, the amount of disulfiram is from about 5 mg to about 500 mg and the amount of cinnamaldehyde is from about 0.01% to about 45% by weight of disulfiram.

In various embodiments, the cinnamaldehyde further potentiates disulfiram's ability to treat acute lung injury (ALI), acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, dry eye, actinic keratosis, alopecia, and/or skin cancer.

In embodiments, the cinnamaldehyde further potentiates disulfiram's ability to inhibit and/or reduce a pathological inflammatory response, alter a T-cell's age, and/or alter mitochondrial function in the cell.

Another aspect of the present disclosure is a method for boosting activity of an immune cell. The method comprises contacting the immune cell with an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde, thereby boosting activity of an immune cell.

In some embodiments, the disulfiram and cinnamaldehyde are included in one composition and the composition consists essentially of disulfiram and cinnamaldehyde. In some cases, the composition further comprises one or more additional ingredients from Table 1. The method may comprise contacting the cell with a first composition consisting essentially of disulfiram and contacting the cell with an at least second composition consisting essentially cinnamaldehyde. Either or both of the first composition and the second composition further comprises one or more additional ingredients from Table 1.

In various embodiments, boosting activity of an immune cell increases an effective immune response against an infectious agent and/or an atypical cell.

In embodiments, boosting activity of an immune cell improves the immune cell's response against a component contained in a vaccine, wherein the component contained in the vaccine is an antigen obtained from, related to, homologous to, or expressed by an infectious agent.

In some embodiments, boosting activity of an immune cell comprises inhibiting a pathological immune response. In some cases, boosting activity of an immune cell minimizes overactive immune cell activity.

In various embodiments, the amount of disulfiram is from about 5 mg to about 500 mg and the amount of cinnamaldehyde is from about 0.01% to about 45% of the weight of the disulfiram.

Yet another aspect of the present disclosure is a composition consisting essentially of an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde. The amount of disulfiram is from about 5 mg to about 500 mg and the amount of cinnamaldehyde is from about 0.01% to about 45% of the of the disulfiram.

It shall be understood that different aspects and/or embodiments of the invention can be appreciated individually, collectively, or in combination with each other. Various aspects and/or embodiments of the invention describe herein may be applied to any of the uses set forth below and in other methods for increasing lifespan in a mammal. Any description herein concerning a specific composition and/or method apply to and may be used for any other specific composition and/or method as disclosed herein. Additionally, any composition disclosed herein is applicable to any herein-disclosed method. In other words, any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1A to FIG. 1D show data obtained when virally infected cells were treated with a disulfiram. FIG. 1A shows cytokine levels from the supernatant of vesicular stomatitis virus encoding a red fluorescent protein (rVSV-ΔG-mCherry)-infected cells (infected at 10×MOI); asterisks indicate statistical significance relative to untreated control cells. Data is normalized by total cell count. In FIG. 1B and FIG. 1C, respectively, show reticularity measurements of mitochondria and aging scores in T cells. In FIG. 1B and FIG. 1C, horizontal bars represent the distribution of untreated controls from younger and older donors; the solid line represents the median and the lower and upper dashed lines represent the 25^(th) and 75^(th) quartiles, respectively. The line graph represents the median and 95% CI for treated cells, with statistical significance relative to untreated control cells indicated by asterisks. In FIG. 1D, “on-age” and “off-age” scores for T cells treated with either disulfiram or dimethyl fumarate. Distributions for younger and older control (untreated) cells are plotted using a Gaussian kernel density estimation. Statistical significance relative to untreated control cells is indicated by the following: *, P<0.5; **, P<0.001; ***, P<0.0001. IL, interleukin; MCP1, monocyte chemoattractant protein 1; MOI, multiplicity of infection; PBMC, peripheral blood mononuclear cell; TNF, tumor necrosis factor.

FIG. 2 shows the effect of cells treated with disulfiram alone, cinnamaldehyde alone, or disulfiram and cinnamaldehyde in combination at different concentrations.

FIG. 3 shows the effect of cells treated with cinnamaldehyde and different concentrations of disulfiram.

FIG. 4A to 4C show synergistic effects of cinnamaldehyde on disulfiram activity. FIG. 4A is a table of synergy ratio of actual/expected effect at each concentration of cinnamaldehyde and disulfiram; cells in grey indicate positive synergy. FIG. 4B and FIG. 4C are graphs showing average synergy at different concentrations of cinnamaldehyde and disulfiram.

FIG. 5 is a table showing the percent difference in IC50 between disulfiram alone vs. disulfiram and cinnamaldehyde at various concentrations or constant ratio (last column). Cinnamaldehyde combined with disulfiram shifts the IC50 to the left relative to disulfiram alone in a dose-dependent manner. cinnamaldehyde has no effect on pyroptosis inhibition or a clear IC50, indicating effects on early inhibition and shifted IC50 is synergistic.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure relates to compositions and methods for increasing lifespan, for preventing or treating a disease including an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system in a mammal. The present disclosure additionally relates to compositions and methods for improving effectiveness of a vaccine in a mammal.

1. Compounds and Compositions

The methods of the present disclosure comprise administering to a mammal a therapeutically effective amount of an active ingredient that is disulfiram and a potentiating ingredient that is cinnamaldehyde or comprise contacting a cell (in vivo, in vitro, or ex vivo) with an active ingredient that is disulfiram and a potentiating ingredient that is cinnamaldehyde.

Disulfiram is a specific inhibitor of an aldehyde-dehydrogenase (ALDH1). Disulfiram was approved by the US Food and Drug Administration in 1951 for alcohol aversion therapy after researchers observed that it induced the effects of a hangover after alcohol consumption. Disulfiram blocks the major metabolic reaction that converts alcohol into acetaldehyde. Disulfiram inhibits pyroptosis of a cell by inhibition of gasdermin D.

As used herein, the term disulfiram includes disulfiram itself and any of its metabolites and/or derivatives. Examples of metabolites include diethyldithiocarbamate, diethyl-amine, and carbon disulfide.

In each aspect and embodiment of the present disclosure, the active agent is disulfiram and the potentiating ingredient is cinnamaldehyde. Cinnamaldehyde has the following chemical identifiers: CAS: 14371-10-9, 104-55-2; DrugBank: DB14184; MedChem: HY-N0609; and SelleckChem: S3763. Cinnamaldehyde is the aldehyde that gives cinnamon its flavor and odor. Cinnamaldehyde occurs naturally in the bark of cinnamon trees and other species of the genus Cinnamomum like camphor and cassia. These trees are the natural source of cinnamon, and the essential oil of cinnamon bark is about 90% cinnamaldehyde. Cinnamaldehyde is also used as a fungicide. Proven effective on over 40 different crops, cinnamaldehyde is typically applied to the root systems of plants. Its low toxicity and well-known properties make it ideal for agriculture. To a lesser extent, cinnamaldehyde is an effective insecticide, and its scent is also known to repel animals like cats and dogs. Cinnamaldehyde is also known as a corrosion inhibitor for steel and other ferrous alloys in corrosive fluids. It can be used in combination with additional components such as dispersing agents, solvents and other surfactants. Concentrated cinnamaldehyde is a skin irritant, and the chemical is toxic in large doses, but no agencies suspect the compound is a carcinogen or poses a long-term health hazard. Most cinnamaldehyde is excreted in urine as cinnamic acid, an oxidized form of cinnamaldehyde. Additional names for cinnamaldehyde include (2E)-3-Phenyl-2-propenal, (2E)-3-Phenylacrylaldehyde, (e)-3-Phenyl-2-propenal, (e)-3-Phenylpropenal, (e)-3-Phenyl-propenal, (e)-Cinnamaldehyde, (e)-Cinnamic aldehyde, (e)-Phenylvinyl aldehyde, 3-Fenylpropenal, 3-Phenyl-2-propen-1-al, 3-Phenyl-2-propenaldehyde, 3-Phenylacrolein, 3-Phenylacrylaldehyde, 3-Phenylprop-2-enal, 3-Phenylprop-2-enaldehyde, 3-Phenylpropenal, Benzylideneacetaldehyde, beta-Phenylacrolein, beta-Phenylcrolein, Cinnamal, Cinnamic aldehyde, Cinnamic aldehyde, (e)-isomer, Cinnamyl aldehyde, Cinnamylaldehyde, fv-Cinnemaldehyde, Supercinnamaldehyde, trans-3-Phenyl-2-propenal, trans-3-Phenylprop-2-enaldehyde, trans-Cinnamaldehyde, trans-Cinnamic aldehyde, and trans-Cinnamylaldehyde.

Cinnamaldehyde is generally recognized as safe (GRAS; e.g., by the FDA), is listed in the FDA inactive ingredient database (IID (see, the World Wide Web at accessdata.fda.gov/scripts/cder/iig/index.cfm), and/or is included in the FDA's Substances Added to Food list (see, the World Wide Web at cfsanappsexternal.fda.gov/scripts/fdcc/?set=FoodSubstances and the regulations set forth in 21 CFR 73, 74, 172, 173, 181, 182, and 184, the contents of each of which is incorporated by reference in its entirety).

As used herein, the term cinnamaldehyde includes cinnamaldehyde itself and any of its metabolites, derivatives, relatives. and/or precursors. An example of a cinnamaldehyde metabolite includes cinnamic acid. An example of a cinnamaldehyde precursor includes cinnamyl alcohol. Examples of other cinnamaldehyde relatives include benzyl cinnamate (which is an ester of cinnamaldehyde), methyl cinnamate (which is an ester of cinnamic acid), and hydrocinnamic acid (which results from hydrogenation of cinnamic acid).

A composition of the present disclosure comprises an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde. A plurality of compositions of the present disclosure may comprise a first composition comprising an active agent that is disulfiram and a second composition comprising a potentiating ingredient that is cinnamaldehyde.

The present disclosure provides methods that comprise administering a therapeutically effective amount of an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde, contacting a cell or immune cell with an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde, a composition comprising an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde, and a plurality of compositions comprising a first composition comprising an active agent that is disulfiram and a second composition comprising a potentiating ingredient that is cinnamaldehyde.

A potentiating ingredient, i.e., cinnamaldehyde, enhances, increases, and/or improves the desirable activity of the active ingredient, i.e., disulfiram. As a non-limiting example, the potentiating ingredient enhances pyroptosis activity of disulfiram.

The potentiating ingredient, i.e., cinnamaldehyde, used in the present disclosure enhances, increases, and/or improves the effectiveness and/or desirable activity of the active ingredient, i.e., disulfiram. Thus, a composition comprising disulfiram alone will be less effective, for example, than a composition comprising disulfiram and its potentiating ingredient cinnamaldehyde. Similarly, a method in which disulfiram is administered alone is less effective than a method in which disulfiram is administered with cinnamaldehyde (either as a single composition or as distinct compositions that are administered contemporaneously or sequentially). In various embodiments, the potentiating ingredient, as disclosed herein, enhances disulfiram's ability to inhibit pyroptosis. In some embodiments, the enhanced, increased, and/or improved effectiveness and/or activity of the active agent, i.e., disulfiram, may be any amount between about 1.1-fold and about 3-fold, e.g., about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3-fold, and any fold therebetween. In embodiments, the enhanced, increased, and/or improved effectiveness and/or activity of the active agent, i.e., disulfiram, may be any amount between about 3-fold and about 5-fold, e.g., about 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5-fold, and any fold therebetween. The enhanced, increased, and/or improved effectiveness and/or activity of the active agent, i.e., disulfiram, may be any amount between about 5-fold and about 15-fold. As examples, the effectiveness may be increased about 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or 15-fold, and any fold therebetween. In some embodiments, the enhanced, increased and/or improved effectiveness and/or activity of the active agent, i.e., disulfiram, is greater than about 15-fold. The increased and/or improved effectiveness may be greater than about 1%, e.g., about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% 80%, 85%, 90%, 95%, or about 100%, and any percentage therebetween.

An enhanced, increased, and/or improved effectiveness and/or activity of the active agent, i.e., disulfiram, may be determined by any assay, phenotype, marker, or indicator demonstrating a desired outcome from a treatment or administration of a composition. As examples, effectiveness and/or activity may be shown as a reduction in markers/indicators of an aging cell, an increase in markers/indicators of a healthy cell, an extension of the active life of a cell, a reduction in apoptosis, increased longevity of a mammal, a reduction in the predicted biological age of a cell, increased titer of antibodies in response to a vaccine, inhibition of pyroptosis in an in vitro assay, an immune profile, and phenotypic changes in a cell that report health and/or activity. Increased and/or improved effectiveness may be objective (e.g., quantifiable) or subjective (e.g., qualifiable).

Because the potentiating ingredient, i.e., cinnamaldehyde, enhances, increases, and/or improve disulfiram's effectiveness and/or activity (e.g., in pyroptosis inhibition), lower doses of disulfiram may be administered to a mammal while still providing a desired outcome. This lower dose may minimize adverse effects resulting from disulfiram administration.

In certain embodiments, disulfiram is administered at a daily dosage of about 5 mg to about 500 mg per day. For example, disulfiram is administered at a total daily dosage of about 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 45, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500 mg per day, and any total dosage therebetween. As examples, the daily dosage may be 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 45-50 mg, 50-55 mg, 55-60 mg, 60-65 mg, 65-70 mg, 70-75 mg, 75-80 mg, 80-85 mg, 85-90 mg, 90-95 mg, 95-100 mg, 100-125 mg, 125-150 mg, 150-175 mg, 175-200 mg, 200-225 mg, 225-250 mg, 250-275 mg, 275-300 mg, 300-325 mg, 325-350 mg, 350-375 mg, 375-400 mg, 400-425 mg, 425-450 mg, 450-475 mg, or 475-500 mg. The disulfiram may be administered 1×, 2×, or 3× per day to achieve the daily dosage. Thus, for a daily dose of 5 mg with a once per day administration, only a single administration of 5 mg will be given; for a daily dose of 5 mg with a twice per day administration, two administrations of about 2.5 mg will be given; and for a daily dose of 5 mg with a thrice per day administration, three administrations of about 1.7 mg will be given. Similarly, for a daily dose of 500 mg with a once per day administration, only a single administration of 500 mg will be given; for a daily dose of 500 mg with a twice per day administration, two administrations of about 250 mg will be given; and for a daily dose of 500 mg with a thrice per day administration, three administrations of about 170 mg will be given. The potentiating ingredient, i.e., cinnamaldehyde, may be administered 1×, 2×, or 3× per day.

In certain embodiments, the potentiating ingredient, i.e., cinnamaldehyde, and the disulfiram are administered in two separate formulations. In certain embodiments, the cinnamaldehyde and the disulfiram are administered in a single formulation.

In certain embodiments, the potentiating ingredient, i.e., cinnamaldehyde, is administered at a ratio of about 1:1 to about 1:3000 moles of cinnamaldehyde to disulfiram. The cinnamaldehyde may be administered at a ratio of about 1:1, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1.09, 1:1.1, 1:1.11, 1:1.12, 1:1.13, 1:1.14, 1:1.15, 1:1.16, 1:1.17, 1:1.18, 1:1.19, 1:1.2, 1:1.21, 1:1.22, 1:1.23, 1:1.24, 1:1.25, 1:1.26, 1:1.27, 1:1.28, 1:1.29, or 1:1.3 moles cinnamaldehyde per mole of disulfiram. The cinnamaldehyde may be administered at a ratio of about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or 1:20 moles cinnamaldehyde per mole of disulfiram. The cinnamaldehyde may be administered at a ratio of about 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190, or 1:200 moles cinnamaldehyde per mole of disulfiram, and any ratio therebetween. As examples, the ratio may be about 1:10-1:15, 1:15-1:20, 1:20-1:25, 1:25-1:30, 1:30-1:35, 1:35-1:40, 1:40-1:45, 1:45-1:50, 1:50-1:55, 1:55-1:60, 1:60-1:65, 1:65-1:70, 1:70-1:75, 1:75-1:80, 1:80-1:85, 1:85-1:90, 1:90-1:95, 1:95-1:100, 1:100-1:125, 1:125-1:150, 1:150-1:175, 1:175-1:200 moles cinnamaldehyde per mole of disulfiram. The cinnamaldehyde may be administered at a ratio of about 1:100, 1:200, 1:300, 1:400, 1:500, 1:600, 1:700, 1:800, 1:900, or 1:1000 moles cinnamaldehyde per mole of disulfiram, and any ratio therebetween. As examples, the ratio may be about 1:100-1:125, 1:125-1:150, 1:150-1:175, 1:175-1:200, 1:200-1:225, 1:225-1:250, 1:250-1:275, 1:275-1:300, 1:300-1:325, 1:325-1:350, 1:350-1:375, 1:375-1:400, 1:400-1:425, 1:425-1:450, 1:450-1:475, 1:475-1:500, 1:500-1:525, 1:525-1:550, 1:550-1:575, 1:575-1:600, 1:600-1:625, 1:625-1:650, 1:650-1:675, 1:675-1:700, 1:700-1:725, 1:725-1:750, 1:750-1:775, 1:775-1:800, 1:800-1:825, 1:825-1:850, 1:850-1:875, 1:875-1:900, 1:900-1:925, 1:925-1:950, 1:950-1:975, or 1:975-1:1000 moles cinnamaldehyde per mole of disulfiram. The cinnamaldehyde may be administered at a ratio of about 1:1000, 1:1100, 1:1200, 1:1300, 1:1400, 1:1500, 1:1600, 1:1700, 1:1800, 1:1900, 1:2000, 1:2100, 1:2200, 1:2300, 1:2400, 1:2500, 1:2600, 1:2700, 1:2800, 1:2900, or 1:3000 moles cinnamaldehyde per mole of disulfiram, and any ratio therebetween. As examples, the ratio may be about 1:1000-1:1100, 1:1100-1:1200, 1:1200-1:1300, 1:1300-1:1400, 1:1400-1:1500, 1:1500-1:1600, 1:1600-1:1700, 1:1700-1:1800, 1:1800-1:1900, 1:1900-1:2000, 1:2000-1:2100, 1:2100-1:2200, 1:2200-1:2300, 1:2300-1:2400, 1:2400-1:2500, 1:2500-1:2600, 1:2600-1:2700, 1:2700-1:2800, 1:2800-1:2900, or 1:2900-1:3000 moles cinnamaldehyde per mole of disulfiram.

In embodiments where the potentiating ingredient, i.e., cinnamaldehyde, and the active agent, i.e., disulfiram, are administered in a single formulation, the amount of cinnamaldehyde is about 0.01% to about 45% of the amount of disulfiram (by weight). The amount of cinnamaldehyde may be about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1% of the weight of the disulfiram. The amount of cinnamaldehyde may be about 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2%, 2.2%, 2.4%, 2.6%, 2.8%, 3%, 3.2%, 3.4%, 3.6%, 3.8%, 4%, 4.2%, 4.4%, 4.6%, 4.8%, 5%, 5.2%, 5.4%, 5.6%, 5.8%, 6%, 6.2%, 6.4%, 6.6%, 6.8%, 7%, 7.2%, 7.4%, 7.6%, 7.8%, 8%, 8.2%, 8.4%, 8.6%, 8.8%, 9%, 9.2%, 9.4%, 9.6%, 9.8%, 10%, of the weight of the disulfiram, and any percentage therebetween. As examples, the percentage may be about 1%-1.5%, 1.5%-2%, 2%-2.5%, 2.5%-3%, 3%-3.5%, 3.5%-4%, 4%-4.5%, 4.5%-5%, 5%-5.5%, 5.5%-6%, 6%-6.5%, 6.5%-7%, 7%-7.5%, 7.5%-8%, 8%-8.5%, 8.5%-9%, 9%-9.5%, or 9.5%-10% of the weight of the disulfiram. The amount of cinnamaldehyde may be about 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, or 45% of the weight of the disulfiram, and any percentage therebetween. As examples, the percentage may be about 10%-15%, 15%-20%, 20%-25%, 25%-30%, 30%-35%, 35%-40%, or 40%-45% of the weight of the disulfiram. In embodiments where the potentiating ingredient, i.e., cinnamaldehyde, and the active agent, i.e., disulfiram, are administered in two formulations, the amount of cinnamaldehyde is about 0.01% to about 45% of the weight of the disulfiram. The amount of cinnamaldehyde may be about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1% of the weight of the disulfiram. The amount of cinnamaldehyde may be about 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2%, 2.2%, 2.4%, 2.6%, 2.8%, 3%, 3.2%, 3.4%, 3.6%, 3.8%, 4%, 4.2%, 4.4%, 4.6%, 4.8%, 5%, 5.2%, 5.4%, 5.6%, 5.8%, 6%, 6.2%, 6.4%, 6.6%, 6.8%, 7%, 7.2%, 7.4%, 7.6%, 7.8%, 8%, 8.2%, 8.4%, 8.6%, 8.8%, 9%, 9.2%, 9.4%, 9.6%, 9.8%, 10%, of the weight of the disulfiram, and any percentage therebetween. As examples, the percentage may be about 1%-1.5%, 1.5%-2%, 2%-2.5%, 2.5%-3%, 3%-3.5%, 3.5%-4%, 4%-4.5%, 4.5%-5%, 5%-5.5%, 5.5%-6%, 6%-6.5%, 6.5%-7%, 7%-7.5%, 7.5%-8%, 8%-8.5%, 8.5%-9%, 9%-9.5%, or 9.5%-10% of the weight of the disulfiram. The amount of cinnamaldehyde may be about 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, or 45% of the weight of the disulfiram, and any percentage therebetween. As examples, the percentage may be about 10%-15%, 15%-20%, 20%-25%, 25%-30%, 30%-35%, 35%-40%, or 40%-45% of the weight of the disulfiram.

In some embodiments, cinnamaldehyde is administered at a daily dosage from about 0.001 mg to about 223 mg. As examples, cinnamaldehyde is administered at a total daily dosage of about 0.001 mg, 0.002 mg, 0.003 mg, 0.004 mg, 0.005 mg, 0.006 mg, 0.007 mg, 0.008 mg, 0.009 mg, or 0.01 mg, and any daily dosage therebetween. As examples, the daily dosage of cinnamaldehyde may be about 0.001-0.002 mg, 0.002-0.003 mg, 0.003-0.004 mg, 0.004-0.005 mg, 0.005-0.006 mg, 0.006-0.007 mg, 0.007-0.008 mg, 0.008-0.009 mg, or 0.009-0.01 mg. The cinnamaldehyde may be administered at a total daily dosage of about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, or 0.1 mg, and any daily dosage therebetween. As examples, the daily dosage of cinnamaldehyde may be about 0.01-0.02 mg, 0.02-0.03 mg, 0.03-0.04 mg, 0.04-0.05 mg, 0.05-0.06 mg, 0.06-0.07 mg, 0.07-0.08 mg, 0.08-0.09 mg, or 0.09-0.1 mg. The cinnamaldehyde may be administered at a total daily dosage of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1 mg, and any daily dosage therebetween. As examples, the daily dosage of cinnamaldehyde may be about 0.1-0.2 mg, 0.2-0.3 mg, 0.3-0.4 mg, 0.4-0.5 mg, 0.5-0.6 mg, 0.6-0.7 mg, 0.7-0.8 mg, 0.8-0.9 mg, or 0.9-1 mg. The cinnamaldehyde may be administered at a total daily dosage of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, and any daily dosage therebetween. As examples, the daily dosage of cinnamaldehyde may be about 1-2 mg, 2-3 mg, 3-4 mg, 4-5 mg, 5-6 mg, 6-7 mg, 7-8 mg, 8-9 mg, or 9-10 mg. The cinnamaldehyde may be administered at a total daily dosage of about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg, and any daily dosage therebetween. As examples, the daily dosage of cinnamaldehyde may be about 10-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, or 90-100 mg. The cinnamaldehyde may be administered at a total daily dosage of about 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, or 223 mg and any daily dosage therebetween. As examples, the daily dosage of cinnamaldehyde may be about 100-110 mg, 110-120 mg, 120-130 mg, 130-140 mg, 140-150 mg, 150-160 mg, 160-170 mg, 170-180 mg, 180-190 mg, 190-200 mg, 200-210 mg, 210-220 mg, or 220-223 mg. The potentiating ingredient, i.e., cinnamaldehyde, may be administered 1×, 2×, or 3× per day to achieve the daily dosage. Thus, for a daily dose of 5 mg with a once per day administration, only a single administration of 5 mg will be given; for a daily dose of 5 mg with a twice per day administration, two administrations of about 2.5 mg will be given; and for a daily dose of 5 mg with a thrice per day administration, three administrations of about 1.7 mg will be given. Similarly, for a daily dose of 223 mg with a once per day administration, only a single administration of 223 mg will be given; for a daily dose of 223 mg with a twice per day administration, two administrations of about 112 mg will be given; and for a daily dose of 223 mg with a thrice per day administration, three administrations of about 74 mg will be given.

Compositions and methods of the present disclosure may further comprise one or more additional ingredients. The additional ingredients may also potentiate the activity of the active agent, i.e., disulfiram. As such, the additional ingredient may be considered a second potentiating ingredient. The additional ingredient may also assist in the potentiating activity of cinnamaldehyde. The additional ingredient may be generally activity inert and, instead, provide other favorable properties to a composition, e.g., acting as a binder, a buffer, a solute, an excipient, and so forth. For example, a composition of the present disclosure may comprise disulfiram and cinnamaldehyde and one or more additional ingredients. When a plurality of compositions is useful in the present disclosure, a first composition may comprise disulfiram, a second composition may comprise cinnamaldehyde, and an at least third composition may comprise one or more additional ingredients. For methods of the present disclosure, a subject may be administered a composition comprising disulfiram, cinnamaldehyde, and one or more additional potentiating ingredients. For other methods of the present disclosure, a subject may be administered a first composition comprising disulfiram, a second composition comprising cinnamaldehyde, and an at least third composition comprising one or more additional ingredients.

An additional ingredient, as used herein, is a compound that is generally recognized as safe (GRAS; e.g., by the FDA), is listed in the FDA inactive ingredient database (IID (see, the World Wide Web at accessdata.fda.gov/scripts/cder/iig/index.cfm), and/or is included in the FDA's Substances Added to Food list (see, the World Wide Web at cfsanappsexternal.fda.gov/scripts/fdcc/?set=FoodSubstances and the regulations set forth in 21 CFR 73, 74, 172, 173, 181, 182, and 184, the contents of each of which is incorporated by reference in its entirety). An additional ingredient may be found in a plurality of the above-mentioned lists/databases. In some instances, an additional ingredient is considered an “inactive ingredient”. An inactive ingredient is any component of a drug product other than the active ingredient (see, the World Wide Web at fda.gov/drugs/drug-approvals-and-databases/inactive-ingredients-approved-drug-products-search-frequently-asked-questions, the contents of which is incorporated by reference in its entirety). In the present disclosure, the active ingredient is disulfiram. In various embodiments of the present disclosure, an additional ingredient is any substance that can intentionally be added to a food as a food additive and which is generally recognized, among qualified experts, as having been adequately shown to be safe under the conditions of its intended use. In particular, additional ingredients are exempted from the usual Federal Food, Drug, and Cosmetic Act (FFDCA) food additive tolerance requirements. An additional ingredient, as used herein, includes both the specific additional ingredient and any of its metabolites and/or their derivatives. Non-limiting examples of a metabolite includes a salt and ester of the additional ingredient. Other variations may include changes in Chirality, Isomers, Hydration states relative to the specific additional ingredient. The usefulness of a metabolite or a derivative of an additional ingredient that is useful in the present disclosure, is well-within the ability of a skilled artisan; such experiments needed to verify that the metabolite or derivative is useful would be similar to the experiments used to verify that the specific additional ingredient is useful, e.g., in the compositions and methods of the present disclosure.

TABLE 1 Illustrative additional ingredients Catalog No Drug Names Target Pathway Biological Activity CAS HY-100489 TBHQ Apoptosis; Apoptosis; TBHQ (tert-Butylhydroquinone) is a widely used 1948-33-0 Autophagy; Autophagy; Nrf2 activator, protects against Doxorubicin ERK; MAPK/ERK (DOX)-induced cardiotoxicity through activation Ferroptosis; Pathway; NF-κB; of Nrf2. TBHQ (tert-Butylhydroquinone) is also Keap1-Nrf2 Stem Cell/Wnt an ERK activator; rescues Dehydrocorydaline (DHC)-induced cell proliferation inhibition in melanoma. HY-101036 Choline (bitartrate) mAChR GPCR/G Protein; Choline (bitartrate) is an essential nutrient, often 87-67-2 Neuronal associated with the B vitamins but not yet Signaling officially defined as a B vitamin Choline (bitartrate) plays an important role in synthesis of the neurotransmitter acetylcholine. HY-101103 (2-Hydroxypropyl)- Others Others (2-Hydroxypropyl)-β-cyclodextrin is a widely 128446-35-5 β-cyclodextrin used drug delivery vehicle to improve the stability and bioavailability. HY-101530 Polyoxyethylene Bacterial; Anti-infection; Polyoxyethylene stearate (POES) is a non-ionic 9004-99-3 stearate P-glycoprotein Membrane emulsifying agent. Transporter/Ion Channel HY-10448 Capsaicin Autophagy; Autophagy; Capsaicin ((E)-Capsaicin) is a mixture of 404-86-4 TRP Channel Membrane Capsaicin and Dihydrocapsaicin. Capsaici is a Transporter/Ion TRPV1 agonist with an EC50 of 0.29 μM in Channel; HEK293 cells. Neuronal Signaling HY-107201 β-Cyclodextrin Influenza Anti-infection β-Cyclodextrin is a cyclic polysaccharide 7585-39-9 Virus composed of seven units of glucose (α-D- glucopyranose) linked by α-(1,4) type bonds. β- Cyclodextrin has often been used to enhance the solubility of drugs. β- Cyclodextrin has anti- influenza virus H1N1 activities. HY-107799 Castor oil Others Others Castor oil is a natural triglyceride and a solvent. 8001-79-4 Castor oil has a laxative effect and induces labor in pregnant females. Castor oil can be used as a solvent, co-solvent, stabilizing agent and polyol for the formation of polymer-nanoparticle composites. HY-107832 Ketoisophorone Others Others Ketoisophorone (4-Oxoisophorone) is a key 1125-21-9 intermediate in the synthesis of carotenoids and flavouring agents. Ketoisophorone is an industrially important cyclic endione. HY-107846 Xylan Others Others Xylan represents the main hemicellulose 9014-63-5 component in the secondary plant cell walls of flowering plants. Xylan is a polysaccharide made from units of xylose and contains predominantly β-D-xylose units linked as in cellulose. HY-109521 Manganous chloride tetrahydrate HY-111095 D-(−)-Lactic Endogenous Metabolic D-(−)-Lactic acid is a normal intermediate in the 10326-41-7 acid Metabolite Enzyme/Protease fermentation (oxidation, metabolism) of sugar. D-(−)-Lactic acid is identified to be a competitive inhibitor of ProDH (proline dehydrogenase) in plants. HY-111830 Lignin Others Others Lignin (Lignine) is a natural complex biopolymer 9005-53-2 with biodegradable and biocompatible. Lignin is the main component of plant cell walls and is a renewable aromatic polymer. Lignin has strongly antioxidant activity. HY-112624 Dextran Others Others Dextran (Dextran 40) has an inhibitory effect on 9004-54-0 thrombocyte aggregation and coagulation factors and is used as a plasma volume expander. HY-113063 3-Methyl-2- Endogenous Metabolic 3-Methyl-2-oxovaleric acid is a neurotoxin, an 1460-34-0 oxovaleric acid Metabolite Enzyme/Protease acidogen, and a metabotoxin, and also an abnormal metabolite that arises from the incomplete breakdown of branched-chain amino acids. HY-114336 Enocyanin Phosphatase Metabolic Enocyanin is an anthocyanin extracted from 11029-12-2 Enzyme/Protease grapes. Enocyanin shows inhibitory effect on the leucine aminopeptidase, acid phosphatase, γ- glutamyl transpeptidase and esterase activity. HY-116084 Trimethylamine Endogenous Immunology/ Trimethylamine N-oxide is a gut microbe- 1184-78-7 N-oxide Metabolite; Inflammation; dependent metabolite of dietary choline and NOD-like Metabolic other trimethylamine-containing nutrients. Receptor (NLR); Enzyme/Protease; Trimethylamine N-oxide induces inflammation NF-κB; Stem by activating the ROS/NLRP3 inflammasome. Reactive Cell/Wnt; TGF- Trimethylamine N-oxide also accelerates Oxygen beta/Smad fibroblast-myofibroblast differentiation and Species; TGF- induces cardiac fibrosis by activating the TGF-β/ beta/Smad smad2 signaling pathway. HY-119309 Sucrose octaacetate Others Others Sucrose octaacetate is an acetylated derivative of 126-14-7 sucrose with an intensely bitter tasting and can be used as bitter tasting surrogate. Sucrose octaacetate can be used as food additive and also used as an adhesive and plasticizer. Sucrose octaacetate also used in many pesticides, insecti- cides, and other toxic products as a deterrent to accidental poisoning. Sucrose octaacetate can also be used as an in situ seed and a soft template to synthesize polyaniline (PANI) nanofibers. HY-124190 Isopropyl myristate 110-27-0 HY-125861 Methyl cellulose Others Others Methylcellulose is a natural polymer which gels 9004-67-5 on heating. Methylcellulose is not toxic. HY-125865 Casein 9000-71-9 HY-128454 Dimethyl trisulfide Endogenous Metabolic Dimethyl trisulfide is an organic chemical 3658-80-8 Metabolite Enzyme/Protease compound and the simplest organic trisulfide found in garlic, onion, broccoli, and similar plants. Dimethyl trisulfide is a cyanide antidote. HY-13211 (E)-2-Decenoic Others Others (E)-2-Decenoic acid is an interesting fatty acid 334-49-6 acid isolated from royal jelly secretions of honey bees. HY-14608 (S)-Glutamic acid Apoptosis; Apoptosis; (S)-Glutamic acid acts as an excitatory transmitter 56-86-0 Endogenous Membrane and an agonist at all subtypes of glutamate Metabolite; Transporter/Ion receptors (metabotropic, kainate, NMDA, and Ferroptosis; Channel; AMPA). (S)-Glutamic acid shows a direct activat- iGluR Metabolic ing effect on the release of DA from dopaminergic Enzyme/Protease; terminals Neuronal Signaling HY-14608A L-Glutamic acid Apoptosis; Apoptosis; L-Glutamic acid monosodium salt acts as an 142-47-2 monosodium salt Ferroptosis; Membrane excitatory transmitter and an agonist at all iGluR Transporter/Ion subtypes of glutamate receptors (metabotropic, Channel; kainate, NMDA, and AMPA). (S)-Glutamic acid Neuronal shows a direct activating effect on the release of Signaling DA from dopaminergic terminals. HY-14617 Paradol COX Immunology/ Paradol is a pungent phenolic substance found in 27113-22-0 Inflammation ginger and other Zingiberaceae plants. Paradol is an effective inhibitor of tumor promotion in mouse skin carcinogenesis, binds to cyclooxy- genase (COX)-2 active site. HY-14621 Zingerone NF-κB NF-κB Zingerone (Vanillylacetone) is a nontoxic meth- 122-48-5 oxyphenol isolated from Zingiber officinale, with potent anti-inflammatory, antidiabetic, anti- lipolytic, antidiarrhoeic, antispasmodic and anti- tumor properties. Zingerone alleviates oxidative stress and inflammation, down-regulates NF-κB mediated signaling pathways. Zingerone acts as an anti-mitotic agent, and inhibits the growth of neuroblastoma cells. HY-15337 Hesperidin Autophagy; Autophagy; Hesperidin (HP) is a bioflavonoid that plays a role 520-26-3 Endogenous Immunology/ in plant defense and is abundant in citrus species, Metabolite; Inflammation; such as grapefruit, lemon and orange. Hesperidin Reactive Metabolic is used effectively as a supplemental agent in Oxygen Enzyme/Protease; complementary therapy protocols, since it possess- Species NF-κB es biological and pharmacological properties as an effective antioxidant, anti-inflammatory, anti- carcinogenic, and anti-hypertensive agent with lipid-lowering activity IC50: hesperidin (IC50 = 116.68 μmo/L)) in vitro: hesperidin and linarin are two of the main constituent of Valeriana's extract exhibiting a high affinity to KATP channel, which are related to the control of Ca++ concentration and release of GABA in synaptic nerve terminal, mainly on cells of SN in vivo: Hesperidin was dissolved in 1% carboxymethyl cellulose (CMC) and administered orally at a dose of 50 mg/kg for 10 consecutive days. In the control group, rats were treated with the corn oil and 1% CMC vehicle. HY-15398 Cholecalciferol Endogenous Metabolic Cholecalciferol(Vitamin D3) is a naturally occur- 67-97-0 Metabolite; Enzyme/Protease; ing form of vitamin D; Reported that upon meta- VD/VDR Vitamin D bolic activation, Cholecalciferol induces cell Related differentiation and prevents proliferation of cancer cells. IC50 value: Target: Vitamin D acts through a receptor that is a member of the ligand-dependent transcription factor superfamily. Modulates the proliferation and differentiation of both normal and cancer cells. Has antiproliferative and antimetastatic effects on breast, colon, and prostate cancer cells. Activated vitamin D receptors in intestine and bone maintain calcium absorbance and homeo- stasis. HY-16637 Folic acid DNA/RNA Cell Cycle/ Folic acid(Vitamin M; Vitamin B9) is a B vitamin; 59-30-3 Synthesis; DNA Damage; is necessary for the production and maintenance Endogenous Metabolic of new cells, for DNA synthesis and RNA Metabolite Enzyme/Protease synthesis. HY-17568 Nonivamide TRP Channel Membrane Nonivamide is a <b<TRPV1 agonist, which 2444-46-4 Transporter/Ion exhibits 4d-EC50 value of 5.1 mg/L in static Channel; toxicity tests. Neuronal Signaling HY-22167 Methyl 2-hydroxy- Others Others Methyl 2-hydroxy-4-methylvalerate is one of 40348-72-9 4-methylvalerate dominant volatile compounds in Zhenjiang aromatic vinegar. Methyl 2-hydroxy-4- methylvalerate is used for charting flavour bio- HY-23539 Sodium thiosulfate synthesis networks of vinegar microbiota. (pentahydrate) HY-33518 2-Pyridinemethane- thiol HY-34439 2,5- Endogenous Metabolic 2,5-Dimethylpyrazine is an endogenous 123-32-0 Dimethylpyrazine Metabolite Enzyme/Protease metabolite. HY-34465 5-Methyl-2- Others Others 5-Methyl-2-thiophenecarboxaldehyde acts as a 13679-70-4 thiophenecarbo- candidate to microscopic third order non-linear xaldehyde optical (NLO) material. HY-34544 2-Hexylthiophene 18794-77-9 HY-34751 2- 636-72-6 Thiophenemethanol HY-40135 L- Endogenous Metabolic L-Hydroxyproline, one of the hydroxyproline 51-35-4 Hydroxyproline Metabolite Enzyme/Protease (Hyp) isomers, is a useful chiral building block in the production of many pharmaceuticals. HY-41417 Octanoic acid Endogenous Metabolic Octanoic acid is an oily liquid with a slightly 124-07-2 Metabolite Enzyme/Protease unpleasant rancid taste and used commercially in the production of esters used in perfumery and also in the manufacture of dyes. HY-41587 Peracetylated 83-87-4 D-glucose HY-42680 (3S,4S,5R)- Endogenous Metabolic (3S,4S,5R)-1,3,4,5,6-Pentahydroxyhexan-2-one is 87-81-0 1,3,4,5,6- Metabolite Enzyme/Protease an endogenous metabolite. Pentahydroxyhexan- 2-one HY-75161 (−)-Menthol Endogenous Membrane (−)-Menthol is a key component of peppermint oil 2216-51-5 Metabolite; Transporter/Ion that binds and activates transient receptor potential TRP Channel Channel; melastatin 8 (TRPM8), a Ca2+-permeable non- Metabolic selective cation channel, to increase [Ca2+]i. Enzyme/Protease; Antitumor activity. Neuronal Signaling HY-76063 Methyl 101-41-7 phenylacetate HY-76225 Monoammonium Others Others Monoammonium glycyrrhizinate hydrate has 53956-04-0 glycyrrhizinate various pharmacological actions such as anti- hydrate inflammatory, antiallergic, antigastriculcer, and antihepatitis activities. HY-76542 Vitamin D2 Endogenous Metabolic Vitamin D2 (Ergocalciferol) is a form of vitamin 50-14-6 Metabolite; Enzyme/Protease; D, used as a vitamin D supplement. VD/VDR Vitamin D Target: Related Ergocalciferol is a secosteroid formed by a photo- chemical bond breaking of a steroid, specifically, by the action of ultraviolet light on ergosterol. HY-77342 Methyl anthranilate 134-20-3 HY-77813 Benzyl Antibiotic; Anti-infection; Benzyl isothiocyanate is a member of natural 622-78-6 isothiocyanate Apoptosis; Apoptosis isothiocyanates with antimicrobial activity. Bacterial Benzyl isothiocyanate potent inhibits cell mobil- ity, migration and invasion nature and matrix metalloproteinase-2 (MMP-2) activity of murine melanoma cells. HY-77995 o-Anisaldehyde 135-02-4 HY-79369 Succinic anhydride 108-30-5 HY-A0100 Thiamine Others Others Thiamine monochloride (Vitamin B1) is an 59-43-8 monochloride essential vitamin that plays an important role in cellular production of energy from ingested food and enhances normal neuronal actives. HY-A0104 Hypromellose Others Others Hypromellose is a water-soluble hydrophilic, non- 9004-65-3 ionic cellulose ether used to form swellable- soluble matrices. HY-B0133 Natamycin Antibiotic; Anti-infection; Natamycin (pimaricin) is an antifungal macrolide 7681-93-8 Endogenous Metabolic polyene that binds to cell membrane sterols. Metabolite; Enzyme/Protease Target: Antifungal Fungal Natamycin (INN), also known as pimaricin and sometimes sold as Natacyn, is a naturally occurr- ing antifungal agent produced during fermentation in soil. Natamycin has a very low solubility in water; however, natamycin is effective at very low levels. There is an MIC (minimum inhibitory concentration) of less than 10 ppm for most molds. Natamycin is classified as a macrolide polyene antifungal and, as a drug, is used to treat fungal keratitis. It is especially effective against Asper- gillus and Fusarium corneal infections. Other common members of the polyene macrolide anti- fungal family are amphotericin B, nystatin, and filipin. Natamycin is also used in the food industry as a natural preservative. Natamycin is used to treat fungal infections, including Candida, Aspergillus, Cephalosporium, Fusarium and Penicillium. It is applied as a cream, in eyedrops, or (for oral infections) in a lozenge. Natamycin shows negligible absorption into the body when administered in these ways. When taken orally, little or none is absorbed from the gastrointestinal tract, making it inappropriate for systemic infections. HY-B0143 Niacin Autophagy; Autophagy; Niacin (Vitamin B3) is a water-soluble vitamin 59-67-6 Endogenous Metabolic and is part of the vitamin B group. Metabolite Enzyme/Protease Target: Others Niacin (also known as vitamin B3 and nicotinic acid) is an organic compound with the formula C6H5NO2 and, depending on the definition used, one of the 20 to 80 essential human nutrients. Not enough niacin in the diet can cause nausea, skin and mouth lesions, anemia, headaches, and tiredness. Chronic Niacin deficiency leads to a disease called pellagra. The lack of niacin may also be observed in pandemic deficiency disease which is caused by a lack of five crucial vitamins: niacin, vitamin C, thiamin, vitamin D and vitamin A, and is usually found in areas of widespread poverty and malnutrition. Niacin has been used for over 50 years to increase levels of HDL in the blood and has been found to decrease the risk of cardiovascular events modestly in a number of controlled human trials. Niacin cannot be directly converted to nicotinamide, but both compounds could be converted to and are precursors of NAD and NADP in vivo. Nicotinic acid, nicotinamide, and tryptophan (via quinoline acid) are co-factors for nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). NAD converts to NADP by phosphoryla- tion in the presence of the enzyme NAD+ kinase. NADP and NAD are coenzyme for many dehydro- genases, participating in many hydrogen transfer processes. NAD is important in catabolism of fat, carbohydrate, protein, and alcohol, as well as cell signaling and DNA repair, and NADP mostly in anabolism reactions such as fatty acid and cholesterol synthesis. High energy requirements (brain) or high turnover rate (gut, skin) organs are usually the most susceptible to their deficiency. HY-B0150 Nicotinamide Endogenous Cell Cycle/ Nicotinamide is a form of vitamin B3 that plays 98-92-0 Metabolite; DNA Damage; essential roles in cell physiology through facilitat- Sirtuin Epigenetics; ing NAD+ redox homeostasis and providing Metabolic NAD+ as a substrate to a class of enzymes that Enzyme/Protease catalyze non-redox reactions. Nicotinamide is an inhibitor of SIRT1. HY-B0166 L-Ascorbic acid Apoptosis; Apoptosis; L-Ascorbic acid is an effective reducing agent and 50-81-7 Reactive Immunology/ donor antioxidant. Oxygen Inflammation; Species Metabolic Enzyme/Protease; NF-κB HY-B0166A L-Ascorbic acid Apoptosis; Apoptosis; L-Ascorbic acid sodium salt is a more bioavailable 134-03-2 sodium salt Reactive Immunology/ form of vitamin C that is an antioxidant agent. Oxygen Inflammation; Species Metabolic Enzyme/Protease; NF-κB HY-B0167 Salicylic acid Apoptosis; Apoptosis; Salicylic acid (2-Hydroxybenzoic acid) inhibits 69-72-7 Autophagy; Autophagy; cyclo-oxygenase-2 (COX-2) activity independent- COX; Immunology/ ly of transcription factor (NF-κB) activation. Endogenous Inflammation; Metabolite; Metabolic Mitophagy Enzyme/Protease HY-B0302 Etidronic acid Apoptosis Apoptosis Etidronic acid (HEDPA) is a bisphosphonate used 2809-21-4 in detergents, water treatment, cosmetics and pharmaceutical treatment. Target: Others Etidronic acid (HEDPA) is a chelating agent and may be added to bind to or counter the effects of substances such as iron, or other metal ions that can occur in the presence of some soaps. Etidronic acid also acts to retard oxidation of fatty acids. For clarification, a chelator, or chelating agent is a binding component added to many cosmetics, beauty products, and water softeners to form multiple bonds with a single metal ion and neutralize it. HY-B0314 Talc Others Others Talc, a naturally occurring mineral composed 14807-96-6 primarily of magnesium, silicon and oxygen, is used in many cosmetics, from baby powder to blush. HY-B0315 Vitamin B12 Endogenous Metabolic Vitamin B12 is a water soluble vitamin with a key 68-19-9 Metabolite Enzyme/Protease role in the normal functioning of the brain and nervous system, and for the formation of blood. HY-B0342 Meglumine Others Others Meglumine is an amino sugar derived from 6284-40-8 sorbitol. Target: Others Meglumine is often used as an excipient in phar- maceuticals and in conjunction with iodinated compounds in contrast media such as diatrizoate meglumine and iodipamide meglumine. HY-B0351 Taurine Autophagy; Autophagy; Taurine is an organic acid widely distributed in 107-35-7 Endogenous Metabolic animal tissues. Metabolite Enzyme/Protease Target: Others Taurine is a major constituent of bile and can be found in the large intestine and accounts for approximately 0.1% of total human body weight. Taurine is present in high concentration in algae and in the animals including insects and arthro- pods, but is generally absent or present in traces in the bacterial and plant kingdoms. In cardiac tissue alone, taurine levels of 20 mM or higher may be found. Taurine availability protects against cholestasis induced by monohydroxy bile acids remains confined to guinea pigs. Oral supplemen- tation of taurine results in increased plasma taurine concentrations and is associated with normaliza- tion of left ventricular function in both groups of cats. Myocardial concentrations of taurine are directly related to plasma concentrations and low plasma concentrations are found to be associated with myocardial failure in cats, proposing a direct link occurs between decreased taurine concentra- tion in the myocardium and decreased myocardial mechanical function. HY-B0361 Aspartame Others Others Aspartame (SC-18862) is an artificial, non- 22839-47-0 saccharide sweetener used as a sugar substitute in some foods and beverages. HY-B0389 Dextrose Endogenous Metabolic Dextrose, a simple sugar (monosaccharide), is an 50-99-7 Metabolite Enzyme/Protease important carbohydrate in biology. Target: Others Dextrose(D-glucose), a simple sugar (mono- saccharide), is an important carbohydrate in biology. HY-B0399 L-Carnitine Endogenous Metabolic L-carnitine (Levocarnitine) is constituent of 541-15-1 Metabolite Enzyme/Protease striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. Target: Others L-carnitine (Levocarnitine) is an endogenous molecule involved in fatty acid metabolism, bio- synthesized within the human body using amino acids: L-lysine and L-methionine, as substrates. L-carnitine (Levocarnitine) can also be found in many foods, but red meats, such as beef and lamb, are the best choices for adding carnitine into the diet. Administering L-carnitine (510 mg/day) to patients with the disease. L-carnitine (Levocarnitine) treatment significantly improved the total time for dozing off during the daytime, calculated from the sleep logs, compared with that of placebo-treated periods. L-carnitine (Levocarnitine) efficiently increased serum acyl- carnitine levels, and reduced serum triglycerides concentration. L-carnitine (Levocarnitine) and its derivatives show promise in the treatment of chronic conditions and diseases associated with mitochondrial dysfunction but further translational studies are needed to fully explore their potential. HY-B0400 D-Sorbitol Endogenous Metabolic D-Sorbitol is a sugar alcohol that is commonly 50-70-4 Metabolite Enzyme/Protease used as a sugar substitute. Target: Others D-Sorbitol occurs naturally and is also produced synthetically from glucose. The food industry uses D-sorbitol as an additive in the form of a sweetener, humectant, emulsifier, thickener, or dietary supple- ment. D-Sorbitol has also been found in cosmetics, paper, and pharmaceuticals. Naturally, D-sorbitol occurs widely in plants via photosynthesis, ranging from algae to higher order fruits of the family Rosaceae. From Wikipedia. HY-B0430A D-Pantothenic acid Apoptosis Apoptosis D-Pantothenic acid sodium (Sodium pantothenate) 867-81-2 (sodium) is an essential trace nutrient that functions as the obligate precursor of coenzyme A (CoA). D- Pantothenic acid sodium plays key roles in myriad biological processes, including many that regulate carbohydrate, lipid, protein, and nucleic acid metabolism. HY-B0456 Riboflavin Endogenous Metabolic Riboflavin is an easily absorbed micronutrient 83-88-5 Metabolite Enzyme/Protease with a key role in maintaining health in humans and other animals Target: Others Riboflavin (vitamin B2) is the direct precursor of redox enzyme cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are essential for multiple cell physiology. Urinary excretion of riboflavin contributes to one- half of the overall removal of riboflavin from plasma. No sex differences were observed for any of the pharmacokinetic variables (P > 0.05). Riboflavin, similar to other vitamins of the B complex, presents anti-inflammatory activity but its full characterization has not yet been carried out. Riboflavin (25, 50 or 100 mg/kg, i.p.), administered immediately and 2 h after the injection of carrageenan, induced antiedema and antinociceptive effects. The antinociceptive effect was not inhibited by the pretreatment with cad- mium sulfate (1 mg/kg), an inhibitor of flavo- kinase. Riboflavin (50 or 100 mg/kg, i.p., 0 and 2 h) also inhibited the fever induced by lipopoly- saccharide (LPS) in rats. Riboflavin is a safe drug, is approved for clinical use and exacerbates the antinociceptive effect of morphine, may warrant clinical trials to assess its potential in the treat- ment of different painful or inflammatory conditions. HY-B0511 Biotin Others Others Biotin is an enzyme co-factor present in minute 58-85-5 amounts in every living cell. Target: Others Biotin is necessary for cell growth, the production of fatty acids, and the metabolism of fats and amino acids. It plays a role in the citric acid cycle, which is the process by which biochemical energy is generated during aerobic respiration. Biotin is a coenzyme for carboxylase enzymes, involved in the synthesis of fatty acids, isoleucine, and valine, and in gluconeogenesis. In addition, biotin is widely used throughout the biotechnology industry to conjugate proteins for biochemical assays. The dietary biotin intake in Western populations has been estimated to be 35 to 70 microg/d (143-287 nmol/d). Recent studies suggest that humans absorb biotin nearly completely. Conditions that may increase biotin requirements in humans include pregnancy, lactation, and therapy with anticonvulsants or lipoic acid. HY-B0647 Butylphthalide Others Others Butylphthalide(3-n-Butylphthalide) is an anti- 6066-49-5 cerebral-ischemia drug; first isolated from the seeds of celery, showed efficacy in animal models of stroke. IC50 value: Target: 3-n-butylphthalide alleviates oxidative stress caused by chronic cerebral ischemia, improves cholinergic function, and inhibits amyloid beta accumulation, thereby improving cerebral neuro- nal injury and cognitive deficits. Intragastric NBP administration to 4-month-old SAMP8 mice for 2 months significantly improved spatial learning a nd memory ability. Moreover, the loss of choline acetyltransferase (ChAT)-positive neurons in the medial septal nucleus and the vertical limb of the diagonal band in SAMP8 mice was slowed down, as was the decline in the protein and mRNA expression of ChAT in the hippocampus, cerebral cortex, and forebrain. HY-B0717 Tocofersolan Others Others Tocofersolan is a synthetic polyethylene glycol 9002-96-4 derivative of α-tocopherol. HY-B0892 Benzyl alcohol Others Others Benzyl alcohol is an aromatic alcohol; a colorless 100-51-6 liquid with a mild pleasant aromatic odor. HY-B0896 Triacetin Endogenous Anti-infection; Triacetin is an artificial chemical compound, is the 102-76-1 Metabolite; Metabolic triester of glycerol and acetic acid, and is the Fungal Enzyme/Protease second simplest fat after triformin. HY-B0914 10-Undecenoic acid Antibiotic; Anti-infection; 10-Undecenoic acid was used as a starting reagent 112-38-9 Endogenous Metabolic in the syntheses of Pheromone (11Z)-hexadecenal. Metabolite; Enzyme/Protease Fungal HY-B0934 Ethylparaben Bacterial Anti-infection Ethylparaben is the ethyl ester of p-hydroxybenzo- 120-47-8 ic acid, used as an antifungal preservative, and food additive HY-B0935 Benzyl benzoate Parasite Anti-infection Benzyl benzoate is used for treatment of paediatric 120-51-4 scabies. HY-B0940 Ethylvanillin Others Others Ethylvanillin is a flavorant, about three times as 121-32-4 potent as vanillin and is used in the production of chocolate. HY-B0964 Riboflavin Endogenous Metabolic Riboflavin phosphate sodium significantly 130-40-5 (phosphate sodium) Metabolite Enzyme/Protease increases in corneal biomechanical stiffness HY-B0985 Phenazopyridine Others Others Phenazopyridine hydrochloride is a chemical, 136-40-3 (hydrochloride) which has a local analgesic effect, often used to alleviate the pain, irritation, discomfort, or urgency caused by urinary tract infections, surgery, or injury to the urinary tract. HY-B0987 Ascorbyl Endogenous Immunology/ Ascothyl palmitate is an ester formed from 137-66-6 palmitate Metabolite; Inflammation; ascorbic acid and palmitic acid creating a fat- Reactive Metabolic soluble form of vitamin C, it is also used as an Oxygen Species Enzyme/Protease; antioxidant food additive. NF-κB HY-B1008 4-Aminobenzoic Endogenous Metabolic 4-Aminobenzoic acid is an intermediate in the 150-13-0 acid Metabolite Enzyme/Protease synthesis of folate by bacteria, plants, and fungi. HY-B1066 Butylhydroxyanis- Ferroptosis; Apoptosis; Butylhydroxyanisole is an antioxidant, consisting 25013-16-5 ole Reactive Immunology/Infl of a mixture of two isomeric organic compounds, Oxygen Species ammation; used as a food additive preservative Metabolic Enzyme/Protease; NF-κB HY-B1092 Gluconate Others Others Gluconate Calcium (Calcium D-gluconate) is a 299-28-5 (Calcium) mineral supplement, manufactured by the neutrali- zation of gluconic acid with lime or calcium carbonate. HY-B1092A Gluconate (sodium) Endogenous Metabolic Gluconate sodium (D-Gluconic acid sodium salt) 527-07-1 Metabolite Enzyme/Protease is a corrosion and scale inhibitor of ordinary steel in simulated cooling water. HY-B1131 Taurocholic acid Endogenous Metabolic Taurocholic acid sodium salt hydrate (Sodium 345909-26-4 (sodium salt Metabolite Enzyme/Protease taurocholate hydrate) is a bile acid involved in the hydrate) emulsification of fats. HY-B1173 (+)-Camphor Bacterial Anti-infection (+)-Camphor is an ingredient in cooking, and as 464-49-3 an embalming fluid for medicinal purposes, HY-B1211 Dehydroacetic Bacterial; Anti-infection Dehydroacetic acid (Biocide 470F), a pyrone 520-45-6 acid Fungal derivative acts as an antibacterial and antifungal agent. Dehydroacetic acid possess phytotoxic activity. HY-B1263 Chlorobutanol Bacterial; Anti-infection Chlorobutanol is a pharmaceutical preservative 57-15-8 Fungal with sedative-hypnotic actions. Chlorobutanol is active against a wide variety of Gram-positive and Gram-negative bacteria, and several mold spores and fungi. HY-B1268 Docusate (Sodium) HSV Anti-infection Docusate Sodium (Dioctyl sulfosuccinate sodium 577-11-7 salt) is a laxative used to for the research of constipation, for constipation due to the use of opiates it may be used with a stimulant laxative, can be taken by mouth or rectally. HY-B1278 D-α-Tocopherol Endogenous Metabolic D-α-Tocopherol acetate (D-Vitamin E acetate) can 58-95-7 acetate Metabolite Enzyme/Protease be hydrolyzed to d-alpha-tocopherol (VE) and absorbed in the small intestine. HY-B1289 Cetylpyridinium Bacterial Anti-infection Cetylpyridinium chloride monohydrate is a 6004-24-6 (chloride cationic quaternary ammonium compound, used in monohydrate) some types of mouthwashes, toothpastes, throat and nasal sprays, is an antiseptic that kills bacteria and other microorganisms, effective in preventing dental plaque and reducing gingivitis. HY-B1337 Choline (chloride) Others Others Choline chloride is an organic compound and a 67-48-1 quaternary ammonium salt, an acyl group acceptor and choline acetyltransferase substrate, also is an important additive in feed especially for chickens where it accelerates growth. HY-B1342 Vitamin A Endogenous Metabolic Retinol, also known as Vitamin A1, has pleiotropic 68-26-8 Metabolite Enzyme/Protease functions including vison, immunity, hemato- poiesis, reproduction, cell differentiation/growth, and development. HY-B1384 Retinyl palmitate Endogenous Metabolic Retinyl palmitate is an ester of Retinol and is the 79-81-2 Metabolite Enzyme/Protease major form of vitamin A found in the epidermis. Retinyl palmitate has been widely used in pharma- ceutical and cosmetic formulations. HY-B1389 Lactitol Others Others Lactitol monohydrate is a disaccharide analogue 81025-04-9 (monohydrate) of lactulose. It has been widely used in the treat- ment of constipation & hepatic encephalopathy. Lactitol is sugar alcohol used as replacement sweeteners. HY-B1391 D-Panthenol Endogenous Metabolic D-Panthenol is the biologically-active alcohol of 81-13-0 Metabolite Enzyme/Protease pantothenic acid, which leads to an elevation in the amount of coenzyme A in the cell. HY-B1411 i-Inositol Endogenous Metabolic i-Inositol is a chemical compound, associated 87-89-8 Metabolite Enzyme/Protease lipids are found in many foods, in particular fruit, especially cantaloupe and oranges. HY-B1425 Ethoxyquin HSP; Reactive Cell Cycle/ Ethoxyquin is an antioxidant which has been used 91-53-2 Oxygen DNA Damage; in animal feed for many years and also an Species Immunology/ inhibitor of heat shock protein 90 (Hsp90). Inflammation; Metabolic Enzyme/Protease; NF-κB HY-B1431 Butylparaben Bacterial; Anti-infection; Butylparaben is an organic compound, has proven 94-26-8 Endogenous Metabolic to be a highly successful antimicrobial preser- Metabolite Enzyme/Protease vative in cosmetics, also used in medication suspensions, and as a flavoring additive in food. HY-B1465 1-Hexadecanol Endogenous Metabolic 1-Hexadecanol is a fatty alcohol, a lipophilic 36653-82-4 Metabolite Enzyme/Protease substrate. HY-B1521 Aluminum Others Others Aluminum Hydroxide is an orally active main 21645-51-2 Hydroxide form of aluminum used as adjuvant. Aluminum hydroxide-based adjuvant researches including the repository effect, pro-phagocytic effect, and acti- vation of the pro-inflammatory NLRP3 pathway. Aluminum Hydroxide also acts as adjuvant to compensate low inherent immunogenicity of HY-B1550 Benzoin subunit vaccines. 119-53-9 HY-B1610 Sodium citrate Bacterial Anti-infection Sodium citrate dehydrate is an anticoagulant and 6132-04-3 (dihydrate) also used as a buffer and food preservatives. HY-B1620 Polyvinylpyrrol Others Others Polyvinylpyrrolidone is a compound which has 9003-39-8 idone been widely tested and used in human and veterinary medicine as an effective wound healing accelerator and disinfectant when combined with iodine and other compounds. HY-B1645 Ferric Ammonium 1185-57-5 Citrate HY-B1651 Iron(II) fumarate Others Others Iron(II) fumarate (Ferrous fumarate) is the iron (II) 141-01-5 salt of fumaric acid. Iron(II) fumarate is an orally active dietary supplement and has the potential for iron deficiency anemia treatment. HY-B1659 Glycerol Endogenous Metabolic Glycerol is a clear, colourless, viscous, sweet- 56-81-5 Metabolite Enzyme/Protease tasting liquid. Glycerol is used in sample prepara- tion and gel formation for polyacrylamide gel electrophoresis. HY-B1673 Pharmatose DCL 14 Endogenous Metabolic Pharmatose DCL 14 is an endogenous metabolite. 64044-51-5 Metabolite Enzyme/Protease HY-B1695 Methyl nicotinate Others Others Methyl nicotinate, the methyl ester of Niacin found 93-60-7 in alcoholic beverages, that is used as an active ingredient as a rubefacient in over-the-counter topical preparations indicated for muscle and joint pain. HY-B1731 Phenyl Salicylate 118-55-8 HY-B1732 DL-3-Phenylalanine 150-30-1 HY-B1779 Sucrose Endogenous Metabolic Sucrose is a disaccharide which is composed of 57-50-1 Metabolite Enzyme/Protease two monosaccharides, glucose and fructose. HY-B1804 Tricaprilin Endogenous Metabolic Tricaprilin (Trioctanoin) is used in study for 538-23-8 Metabolite Enzyme/Protease patients with mild to moderate Alzheimer's disease and has a role as an anticonvulsant and a plant metabolite. HY-B1812 1,2- Others Others 1,2-Dimethoxybenzene is an naturally occurring 91-16-7 Dimethoxybenzene insect attractant. HY-B1960 Canthaxanthin Reactive Immunology/ Canthaxanthin is a red-orange carotenoid with 514-78-3 Oxygen Inflammation; various biological activities, such as antioxidant, Species Metabolic antitumor properties. Enzyme/Protease; NF-κB HY-B2118 Pancreatin Others Others Pancreatin is the porcine pancreas extract (PPE) 8049-47-6 which contains the main pancreatic digestive enzymes. HY-B2122 Maltitol Others Others Maltitol is a sugar alcohol used as a sugar substi- 585-88-6 tute. It has 75-90% of the sweetness of sucrose (table sugar) and nearly identical properties. Maltitol may also be used as a plasticizer in gelatin capsules, as an emollient, and as a humectant. HY-B2123 Lactose Endogenous Metabolic Lactose, a major sugar in the milk of most 63-42-3 Metabolite Enzyme/Protease species, could regulate human's intestinal microflora. HY-B2136 Tannic acid Potassium Membrane Tannic acid is a novel hERG channel blocker with 1401-55-4 Channel Transporter/Ion IC50 of 3.4 μM. Channel HY-B2163 Astaxanthin PPAR; Cell Cycle/DNA Astaxanthin, a red dietary carotenoid isolated from 472-61-7 Reactive Damage; Haematococcus pluvialis, is a modulator of PPARγ Oxygen Immunology/ and a potent antioxidant with antiproliferative, Species Inflammation; neuroprotective and anti-inflammatory activity. Metabolic Astaxanthin has potential in the study of various Enzyme/Protease; diseases, such as cancers and Parkinson's disease, NF-κB cardiovascular disease. Due to its bright red colour, Astaxanthin could be used as a food colorant in animal feeds. HY-B2200 Calcium citrate 5785-44-4 tetrahydrate HY-B2201 Trisodium citrate 68-04-2 HY-B2203 Calcium glycerol 27214-00-2 phosphate HY-B2205 Magnesium silicate 1343-88-0 HY-B2217 Calcium hydroxide 1305-62-0 HY-B2218 Magnesium 1309-42-8 hydroxide HY-B2219 Stearic acid Endogenous Metabolic Stearic acid is a long chain dietary saturated fatty 57-11-4 Metabolite Enzyme/Protease acid which exists in many animal and vegetable fats and oils. HY-B2221 Cellulose 9004-34-6 HY-B2221B Hydroxyethyl Others Others Hydroxyethyl cellulose is a non-ionic, water 9004-62-0 cellulose soluble, modified cellulose polymer used as a thickening agent for aqueous cosmetic and personal care formulations. HY-B2223 Thiamine nitrate Others Others Thiamine nitrate is an essential vitamin which 532-43-4 can enhance normal neuronal actives. HY-B2225 Starch 9005-25-8 HY-B2226 Sodium copper HIV; Anti-infection Sodium copper chlorophyllin B exerts antiviral 28302-36-5 chlorophyllin B Influenza activities against Influenza virus and HIV with Virus IC50s of 50 to 100 μM for both of them. HY-B2227A Calcium lactate 814-80-2 HY-B2228 Proteinase Others Others Proteinase refers to the enzymes with proteolytic 9001-92-7 activity. HY-B2232 Benzalkonium Bacterial Anti-infection Benzalkonium chloride is a potent anti-microbial 8001-54-5 (chloride) agent, used as a preservative in eye drops. HY-B2235 Lecithin Endogenous Metabolic Lecithin is regarded as a safe, conventional phos- 8002-43-5 Metabolite Enzyme/Protease pholipid source. Phospholipids are reported to alter the fatty acid composition and micro- structure of the membranes in animal cells. HY-B2237 Lysozyme from Bacterial Anti-infection Lysozyme from chicken egg white is a bactericidal 12650-88-3 chicken egg white enzyme present in chicken eggs, and it lyses gram-positive bacteria. IC50 & Target: Bacteria In vitro: Lysozyme is an ubiquitous enzyme. The hen egg is the most abundant source of lysozyme, which constitutes approximately 3.4% of the albumen proteins. Lysozyme is a natural anti- microbial that hydrolyzes the β(1-4) glycosidic linkage between N-acetylmuramic acid and N- acetylglucosamine found in the peptidoglycan layer of the bacterial cell wall and causing cell lysis. The bactericidal effect of lysozyme is primarily limited to gram-positive bacteria, includ- ing pathogens such as Listeria monocytogenes and certain Clostridium species as well as some spoilage organisms, including thermophilic spore- forming bacteria and certain yeasts. The gram- negative bacteria are more resistant to lysozyme action because of their complex cell wall structure. HY-B2241 Aluminum 7784-24-9 potassium disulfate dodecahydrate HY-B2242 Calcium phosphate 7757-93-9 HY-B2243 Dihydrogen 7558-80-7 monosodium phosphate HY-D0195 Acesulfame 55589-62-3 (potassium) HY-D0227 Trometamol Others Others Trometamol is a biologically inert amino alcohol 77-86-1 of low toxicity, which buffers carbon dioxide and acids in vitro and in vivo. Trometamol is an effective amine compound for pH control in the physiological range. HY-D0249 Sunset Yellow Others Others Sunset Yellow FCF is a petroleum-derived orange 2783-94-0 FCF azo dye with a pH dependent maximum absorption at about 480 nm at pH 1 and 443 nm at pH 13. Sunset Yellow is used in food, cosmetics, and drugs. HY-D0257 Tartrazine Others Others Tartrazine is a synthetic lemon yellow azo dye 1934-21-0 primarily used as a food coloring. Tartrazine is water-soluble and has a maximum absorbance in an aqueous solution at 425 nm. HY-D0259 Erythrosine B Others Others Erythrosine B is an artificial dye widely used in 16423-68-0 the food and textile industries. Erythrosine B is also a novel photosensitizer which has been used to develop animal models. HY-D0307A Amaranth Others Others Amaranth is a dark red to purple azo dye used as 915-67-3 a food dye and to color cosmetics. Amaranth is an anionic dye. It can be applied to natural and synthetic fibers, leather, paper, and phenol- formaldehyde resins. HY-D0833 Calcium 7758-87-4 orthophosphate HY-D0835 Hydroxylapatite HY-D0887 Disodium Others Others Disodium 5′-inosinate, obtained from bacterial 4691-65-0 5′-inosinate fermentation of sugars, is as a food additive and often found in a variety of other snacks. HY-D0914 Fast Green FCF Others Others Fast Green FCF is a sea green triarylmethane food 2353-45-9 dye. Fast Green FCF is used as a quantitative stain for histones at alkaline pH after acid extraction of DNA. It is also used as a protein stain in electro- phoresis. Its absorption maximum is at 625 nm. HY-D0915 Brilliant Blue FCF Others Others Brilliant Blue FCF has the appearance of a 3844-45-9 reddish-blue powder. It is soluble in water, and the solution has a maximum absorption at about 628 nanometers. It is a synthetic dye produced using aromatic hydrocarbons from petroleum, is a colorant for foods and other substances. HY-D1005 Poloxamer 407 Others Others Poloxamer 407 is a nonionic surfactant that is 9003-11-6 100% active and relatively non-toxic to cells at low concentrations, and frequently used with dye AM esters such as Indo-1 AM, Fura-2 AM, Calcein AM, Fluo-3 AM, Fluo-4 AM, Quest Fluo-8? AM and Quest Rhod-4? AM, etc. to improve their water solubility. HY-D1005A Poloxamer 188 Others Others Poloxamer 188 is a nonionic linear copolymer 691397-13-4 with surfactant properties. Poloxamer 188 exhibits anti-thrombotic, anti-inflammatory, and cytoprotective activities in various tissue injury models. HY-ER013 Sodium carbonate 497-19-8 HY-I0301 D-(+)-Glucono-1,5- Endogenous Immunology/ D-(+)-Glucono-1,5-lactone is a polyhydroxy 90-80-2 lactone Metabolite; Inflammation; (PHA) that is capable of metal chelating, Reactive Metabolic moisturizing and antioxidant activity. Oxygen Enzyme/Protease; Species NF-κB HY-I0501 2′-Aminoacetophen- Bacterial Anti-infection 2′-Aminoacetophenone is an aromatic compound 551-93-9 one containing a ketone substituted by one alkyl group, and a phenyl group. 2′-Aminoacetophenone can be used as a breath biomarker for the detection of Ps. Aeruginosa infections in the cystic fibrosis lung. HY-N0060A Ferulic acid Endogenous Immunology/ Ferulic acid sodium is a novel fibroblast growth 24276-84-4 (sodium) Metabolite; Inflammation; factor receptor 1 (FGFR1) inhibitor with IC50s of FGFR; Reactive Metabolic 3.78 and 12.5 μM for FGFR1 and FGFR2, Oxygen Species Enzyme/Protease; respectively. NF-κB; Protein Tyrosine Kinase/ RTK HY-N0098 Vanillin Endogenous Metabolic Vanillin (p-Vanillin) is a single molecule extracted 121-33-5 Metabolite Enzyme/Protease from vanilla beans and also a popular odor used widely in perfume, food and medicine. HY-N0119 Naringin NF-κB NF-κB Naringin Dihydrochalcone is an artificial sweeten- 18916-17-1 Dihydrochalcone er derived from naringin. Naringin is a major flavanone glycoside obtained from tomatoes, grapefruits, and many other citrus fruits. Naringin exhibits biological properties such as antioxidant, anti-inflammatory, and antiapoptotic activities. Naringin suppresses NF-κB signaling pathway. HY-N0129 Sclareolide Bacterial Anti-infection Sclareolide is isolated from the flower of Salvia 564-20-5 sclarea with antibacterial and cytotoxic activities. HY-N0138 Theobromine Adenosine GPCR/G Protein; Theobromine is a methylxanthine found in cacao 83-67-0 Receptor; Metabolic beans which can inhibit adenosine receptor A1 Endogenous Enzyme/Protease (AR1) signaling Metabolite HY-N0142 Phloretin Endogenous Membrane Phloretin (NSC 407292; RJC 02792) is a flavonoid 60-82-2 Metabolite; Transporter/Ion extracted from Prunus mandshurica, has anti- GLUT; SGLT Channel; inflammatory activities. Phloridzin is a specific, Metabolic competitive and orally active inhibitor of sodium/ Enzyme/Protease glucose cotransporters in the intestine (SGLT1) and kidney (SGLT2). Phloretin inhibits Yeast- made GLUT1 as well as Human erythrocyte GLUT1 with IC50values of 49 μM and 61 μM, respectively. Phloretin has the potential for the treatment of rheumatoid arthritis (RA)?and allergic airway inflammation. HY-N0144 Piperine Autophagy; Autophagy; Piperine, a natural alkaloid isolated from Piper 94-62-2 Endogenous Membrane nigrum L, inhibits P-glycoprotein and CYP3A4 Metabolite; Transporter/Ion activities with an IC50 value of 61.94 ± 0.054 P-glycoprotein Channel; μg/mL in HeLa cell. Metabolic Enzyme/Protease HY-N0148 Rutin Autophagy; Anti-infection; Rutin, a naturally occurring flavonoid glycoside, 153-18-4 Endogenous Autophagy; has antioxidant, anti-inflammatory, anti-allergic, Metabolite; Immunology/ xanti-angiogenic and antiviral properties. Influenza Inflammation; Virus; Metabolic Reactive Enzyme/Protease; Oxygen NF-κB Species HY-N0154 Neohesperidin Reactive Immunology/ Neohesperidin dihydrochalcone is a synthetic 20702-77-6 dihydrochalcone Oxygen Inflammation; glycoside chalcone, is added to various foods and Species Metabolic beverages as a low caloric artificial sweetener. Enzyme/Protease; NF-κB HY-N0163 Magnolol Autophagy; Anti-infection; Magnolol, a natural lignan isolated from the stem 528-43-8 Bacterial; Autophagy; Cell bark of Magnolia officinalis, is a dual agonist of PPAR; Cycle/DNA both RXRα and PPARγ, with EC50 values of 10.4 RAR/RXR Damage; μM and 17.7 μM, respectively. Metabolic Enzyme/Protease HY-N0168 Hesperetin Apoptosis; Apoptosis; Hesperetin is a natural flavanone, and acts as a 520-33-2 Autophagy; Autophagy; potent and broad-spectrum inhibitor against human p38 MAPK MAPK/ERK UGT activity. Hesperetin induces apoptosis via Pathway p38 MAPK activation. HY-N0184 Glycyrrhizic acid Virus Protease Anti-infection Glycyrrhizic acid is a triterpenoid saponinl, acting 1405-86-3 as a direct HMGB1 antagonist, with anti-tumor, anti-diabetic activities. HY-N0198 Nordihydroguaiarc- Autophagy; Apoptosis; Nordihydroguaiaretic acid is a 5-lipoxygenase 500-38-9 tic acid Ferroptosis; Autophagy; (5LOX) (IC50 = 8 μM) and tyrosine kinase Lipoxygenase Metabolic inhibitor. Enzyme/Protease HY-N0215 L-Phenylalanine Calcium Membrane L-Phenylalanine ((S)-2-Amino-3-phenylpropionic 63-91-2 Channel; Transporter/Ion acid) is an essential amino acid isolated from Endogenous Channel; Escherichia coli. L-Phenylalanine is a α2δ Metabolite; Metabolic subunit of voltage-dependent Ca+ channels iGluR Enzyme/Protease; antagonist with a Ki of 980nM. L-phenylalanine is Neuronal a competitive antagonist for the glycine- and Signaling glutamate-binding sites of N-methyl-D-aspartate receptors (NMDARs) (KB of 573 μM) and non- NMDARs, respectively. L-Phenylalanine is widely used in the production of food flavors and pharmaceuticals. HY-N0216 Benzoic acid Bacterial; Anti-infection; Benzoic acid is an aromatic alcohol existing 65-85-0 Endogenous Metabolic naturally in many plants and is a common Metabolite; Enzyme/Protease additive to food, drinks, cosmetics and other Fungal products. It acts as preservatives through inhibit- ing both bacteria and fungi. HY-N0229 L-Alanine Endogenous Metabolic L-Alanine is a non-essential amino acid, involved 56-41-7 Metabolite Enzyme/Protease in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and central nervous system. HY-N0230 β-Alanine Endogenous Metabolic β-Alanine is a non-essential amino acid that is 107-95-9 Metabolite Enzyme/Protease shown to be metabolized into carnosine, which functions as an intracellular buffer. HY-N0264 Tetramethylpyra- Apoptosis Apoptosis Tetramethylpyrazine (Ligustrazine), an alkyl- 1124-11-4 zine pyrazine isolated from Ligusticum wallichii (Chuan Xiong), is present in french fries, bread, cooked meats, tea, cocoa, coffee, beer, spirits, peanuts, filberts, dairy products and soy products as fragrance and flavouring ingredienexhibits. Tetramethylpyrazine (Ligustrazine) also has potential nootropic and anti-inflammatory activities in rats. HY-N0287 Lycopene Reactive Immunology/ Lycopene is naturally occurring carotenoids 502-65-8 Oxygen Inflammation; found in tomato, tomato products, and in other Species Metabolic red fruits and vegetables; exhibits antioxidant Enzyme/Protease; effects. NF-κB HY-N0294 Protocatechuic acid Others Others Protocatechuic acid is a phenolic compound 99-50-3 which exhibits neuroprotective effect. HY-N0324 Cholic acid Endogenous Metabolic Cholic acid is a major primary bile acid 81-25-4 Metabolite Enzyme/Protease produced in the liver and usually conjugated with glycine or taurine. It facilitates fat absorp- tion and cholesterol excretion. HY-N0325 DL-Methionine 59-51-8 HY-N0326 L-Methionine Endogenous Metabolic L-Methionine is the L-isomer of Methionine, an 63-68-3 Metabolite Enzyme/Protease essential amino acid for human development. Methionine acts as a hepatoprotectant. HY-N0336 3- Parasite Anti-infection 3-Butylidenephthalide (Butylidenephthalide) is 551-08-6 Butylidenephthalide a phthalic anhydride derivative identified in Ligusticum chuanxiong Hort, and has larvicidal activity (LC50 of 1.56 mg/g for Spodoptera litura larvae). HY-N0337 Eugenol Apoptosis; Anti-infection; Eugenol is an essential oil found in cloves with 97-53-0 Bacterial; Apoptosis; antibacterial, anthelmintic and antioxidant Ferroptosis; Immunology/ activity. Eugenol is shown to inhibit lipid Parasite; Inflammation; peroxidation. Reactive Metabolic Oxygen Species Enzyme/Protease; NF-κB HY-N0349 Methyl Paraben Bacterial; Anti-infection; Methyl Paraben, isolated from the barks of 99-76-3 Endogenous Metabolic Tsuga dumosa the methyl ester of p- Metabolite Enzyme/Protease hydroxybenzoic acid, is a standardized chemical allergen. Methyl Paraben is a stable, non-volatile compound used as an antimicrobial preservative in foods, drugs and cosmetics. The physiologic effect of Methyl Paraben is by means of increased histamine release, and cell- mediated immunity HY-N0367 Trans-Anethole Endogenous Metabolic Trans-Anethole ((E)-Anethole), a phenylpropene 4180-23-8 Metabolite Enzyme/Protease derivative isolated from Pimpinella, shows estro- genic activity at lower concentrations and cyto- toxic at higher concentrations in cancer cell lines. Trans-Anethole ((E)-Anethole) contributes a large component of the odor and flavor of anise and fennel, anise myrtle, liquorice, camphor, magnolia blossoms, and star anise. HY-N0368 Linalool Apoptosis; Apoptosis; Linalool is natural monoterpene in essential olis 78-70-6 Endogenous Membrane of coriander, acts as a competitive antagonist of Metabolite; Transporter/Ion Nmethyl d-aspartate (NMDA) receptor, with iGluR Channel; anti-tumor, anti-cardiotoxicity activity. Linalool Metabolic is a PPARα ligand that reduces plasma TG levels Enzyme/Protease; and rewires the hepatic transcriptome and plasma Neuronal metabolome. Signaling HY-N0378 D-Mannitol Apoptosis; Apoptosis; D-Mannitol is an osmotic diuretic agent and a 69-65-8 Endogenous Metabolic weak renal vasodilator. Metabolite Enzyme/Protease Target: Others D(−)Mannitol is a sugar alcohol that can be used as an inert osmotic control substance. The uptake and phosphorylation of d-mannitol is catalyzed by the mannitol-specific phosphoenolpyruvate- dependent phosphotransferase systems (PTS). Mannitol can interact with neutrophils and monocytes. Experiments have shown that it is able to decrease neutrophil apoptosis in vitro. The compound has been used in studies as a stimulator of cecal microbial growth and cellulo- lytic activity in rabbits. It has been observed that mannitol can lower the fat digestibility and body fat accumulation in both normal and cecectomi- zed rats, as well as upregulate monocyte HLA- DR, monocyte and neutrophil CD11b. Studies show that the mannitol operon is repressed by the transcription factor, mannitol operon repressor (Mt1R) in Escherichia coli. HY-N0390 L-Glutamine Endogenous Apoptosis; L-Glutamine is a non-essential amino acid 56-85-9 Metabolite; GPCR/G Protein; present abundantly throughout the body and is Ferroptosis; Metabolic involved in gastrointestinal disorders. mGluR Enzyme/Protease; Target: mGluR Neuronal Glutamine (abbreviated as Gln or Q) is one of Signaling the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid, but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal dis- orders. Its side-chain is an amide formed by replacing the side-chain hydroxyl of glutamic acid with an amine functional group, making it the amide of glutamic acid. Its codons are CAA and CAG. In human blood, glutamine is the most abundant free amino acid, with a concentration of about 500-900 μmol/L. Glutamine is synthesized by the enzyme glutamine synthetase from gluta- mate and ammonia. The most relevant glutamine- producing tissue is the muscle mass, accounting for about 90% of all glutamine synthesized. Glutamine is also released, in small amounts, by the lung and the brain. Although the liver is capable of relevant glutamine synthesis, its role in glutamine metabolism is more regulatory than producing, since the liver takes up large amounts of glutamine derived from the gut. The most eager consumers of glutamine are the cells of intestines, the kidney cells for the acid-base balance, activated immune cells, and manycancer cells. In respect to the last point mentioned, different glutamine analogues, such as DON, Azaserine or Acivicin, are tested as anticancer drugs. HY-N0394 L-Cystine Endogenous Apoptosis; L-Cystine is an amino acid and intracellular 56-89-3 Metabolite; Metabolic thiol, which plays a critical role in the regulation Ferroptosis Enzyme/Protease of cellular processes. HY-N0411 β-Carotene Endogenous Metabolic β-Carotene (Provitamin A) is an organic com- 7235-40-7 Metabolite Enzyme/Protease pound and classified as a terpenoid. It is a precursor (inactive form) of vitamin A HY-N0420 Succinic acid Endogenous Metabolic Succinic acid is an intermediate product of the 110-15-6 Metabolite Enzyme/Protease tricarboxylic acid cycle, as well as one of fer- mentation products of anaerobic metabolism. HY-N0445 2-Hydroxy-4- Tyrosinase Metabolic 2-Hydroxy-4-methoxybenzaldehyde, a chemical 673-22-3 methoxybenzalde Enzyme/Protease compound and an isomer of Vanillin, could be hyde used to synthesis Urolithin M7. 2-hydroxy-4- methoxybenzaldehyde is a potent tyrosinase inhibitor from three East African medicinal plants, Mondia whitei, Rhus vulgaris Meikle, and Sclerocarya caffm Sond. HY-N0455 L-Arginine Endogenous Immunology/ L-Arginine is the nitrogen donor for synthesis of 74-79-3 Metabolite; Inflammation; nitric oxide, a potent vasodilator that is deficient NO Synthase Metabolic during times of sickle cell crisis. Enzyme/Protease Target: Others L-Arginine is an β-amino acid. It was first isolated in 1886. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that code for arginine during protein synthesis. In mammals, arginine is classified as a semiessential or conditionally essential amino acid, depending on the develop- mental stage and health status of the individual. L-Arginine is associated with a decrease in cardiac index while stroke index is maintained in patients with severe sepsis. Resolution of shock at 72 hours is achieved by 40% and 24% of the patients in the L-Arginine and placebo cohorts, respectively. L-Arginine (450 mg/kg during a 15-minute period) amplifies and sustains the hyperemia (38%) and increases absolute brain blood flow after eNOS upregulation by chronic simvastatin treatment (2 mg/kg subcutaneously, daily for 14 days) in SV-129 mice. HY-N0466 Rebaudioside A Endogenous Metabolic Rebaudioside A is a steviol glycoside, β-gluco- 58543-16-1 Metabolite; Enzyme/Protease sidase inhibitor with IC50 of 35.01 μg/ml.can Glucosidase inhibit ATP-sensitive K+-channels. Target: β-glucosidase IC 50: 35.01 ug/mL In vitro: rebaudioside A stimulat the insulin secretion from MIN6 cells in a dose- and glucose-dependent manner. In conclusion, the insulinotropic effect of rebaudioside A is mediated via inhibition of ATP-sensitive K+- channels and requires the presence of high glucose. In vivo: in vivo mouse micronucleus test at doses up to 750 mg/kg bw and an un- scheduled DNA synthesis test in rats at doses up to 2000 mg/kg bw, rebaudioside A do not cause any genotoxic effects at any of the doses tested. HY-N0467 Rebaudioside C Endogenous Metabolic Rebaudioside C(Dulcoside B) is used as natural 63550-99-2 Metabolite Enzyme/Protease sweeteners to diabetics and others on carbo- hydrate-controlled diets. HY-N0469 L-Lysine Endogenous Anti-infection; L-lysine is an essential amino acid with 56-87-1 Metabolite; Metabolic important roles in connective tissues and Virus Protease Enzyme/Protease carnitine synthesis, energy production, growth in children, and maintenance of immune functions. HY-N0473 L-Tyrosine Endogenous Metabolic L-Tyrosine is a non-essential amino acid which 60-18-4 Metabolite Enzyme/Protease can inhibit citrate synthase activity in the posterior cortex. HY-N0486 L-Leucine mTOR PI3K/Akt/mTOR L-Leucine is an essential branched-chain amino 61-90-5 acid (BCAA), which activates the mTOR signaling pathway. HY-N0524 Propyl gallate Others Others Propyl gallate is a common food antioxidant. 121-79-9 Propyl gallate can inhibit the production of acrolein, glyoxal and methylglyoxal. HY-N0537 Xylose Endogenous Metabolic Xylose, a natural product, can be catalyzed into 58-86-6 Metabolite Enzyme/Protease xylulose by xylose isomerase, and it is the key step for anaerobic ethanolic fermentation of xylose. HY-N0538 Xylitol Autophagy; Autophagy; Xylitol is a chemical categorized as a poly- 87-99-0 Endogenous Metabolic alcohol or sugar alcohol. Metabolite Enzyme/Protease Target: Others Xylitol is a chemical categorized as a poly- alcohol or sugar alcohol (alditol). Xylitol has the formula (CHOH)3(CH2OH)2 and is an achiral isomer of pentane-1,2,3,4,5-pentol. Xylitol is used as a diabetic sweetener which is roughly as sweet as sucrose with 33% fewer calories. Unlike other natural or synthetic sweeteners, xylitol is actively beneficial for dental health by reducing caries to a third in regular use and helpful to remineralization. Xylitol is naturally found in low concentrations in the fibers of many fruits and vegetables, and can be extracted from various berries, oats, and mushrooms, as well as fibrous material such as corn husks and sugar cane bagasse and birch. HY-N0593 Deoxycholic acid Endogenous GPCR/G Protein; Deoxycholic acid is specifically responsible for 83-44-3 Metabolite; Metabolic activating the G protein-coupled bile acid GPCR19 Enzyme/Protease receptor TGR5 that stimulates brown adipose tissue (BAT) thermogenic activity. HY-N0614 Sucralose Endogenous Metabolic Sucralose is an intense organochlorine artificial 56038-13-2 Metabolite Enzyme/Protease sweetener. HY-N0623 L-Tryptophan Endogenous Metabolic L-Tryptophan (Tryptophan) is an essential 73-22-3 Metabolite Enzyme/Protease amino acid that is the precursor of serotonin, melatonin, and vitamin B3. HY-N0626 Sorbic acid Antibiotic; Anti-infection; Sorbic acid, isolated from Sorbus aucuparia, is 110-44-1 Bacterial; Metabolic a naturally occurring, highly efficient, and Endogenous Enzyme/Protease nonpoisonous?food preservative.?Sorbic acid Metabolite; generally is an effective inhibitor of most molds Fungal and yeasts and some bacteria. HY-N0633 Muscone Interleukin Apoptosis; Muscone is the main active monomer of 541-91-3 Related; NF-κB; Immunology/ traditional Chinese medicine musk. Muscone NOD-like Inflammation; inhibits NF-κB and NLRP3 inflammasome Receptor NF-κB activation. Muscone remarkably decreases the (NLR); TNF levels of inflammatory cytokines (IL-1β, TNF-α Receptor and IL-6), and ultimately improves cardiac function and survival rate. HY-N0650 L-Serine Endogenous Metabolic L-Serine ((−)-Serine; (S)-Serine), one of the so- 56-45-1 Metabolite Enzyme/Protease called non-essential amino acids, plays a central role in cellular proliferation. HY-N0658 L-Threonine Endogenous Metabolic L-Threonine is a natural amino acid, can be 72-19-5 Metabolite Enzyme/Protease produced by microbial fermentation, and is used in food, medicine, or feed. HY-N0666 L-Aspartic acid Endogenous Metabolic L-Aspartic acid is is an amino acid, shown to be 56-84-8 Metabolite Enzyme/Protease a suitable prodrug for colon-specific drug deliverly. HY-N0667 L-Asparagine Endogenous Metabolic L-Asparagine ((−)-Asparagine) is a non-essential 70-47-3 Metabolite Enzyme/Protease amino acid that is involved in the metabolic control of cell functions in nerve and brain tissue. HY-N0679 Retinyl acetate Others Others Retinyl acetate is a synthetic acetate ester form 127-47-9 derived from retinol and has potential antineo- plastic and chemo preventive activities. HY-N0680 Thiamine Apoptosis; Anti-infection; Thiamine hydrochloride is an essential micro- 67-03-8 hydrochloride Endogenous Apoptosis; nutrient needed as a cofactor for many central Metabolite; Metabolic metabolic enzymes. HBV Enzyme/Protease HY-N0681 D-Pantothenic acid Apoptosis; Apoptosis; D-Pantothenic acid hemicalcium salt (Vitamin 137-08-6 (hemicalcium salt) Endogenous Metabolic B5 calcium salt), a vitamin, can reduce the Metabolite Enzyme/Protease patulin content of the apple juice. IC50 value: Target: In vitro: In human dermal fibroblasts from three different donors, D-Pantothenic acid hemi- calcium salt accelerates the wound healing process by increasing the number of migrating cells, their distance and hence their speed. In addition, cell division is increased and the protein synthesis changed. In vivo: HY-N0682 Pyridoxine Endogenous Metabolic Pyridoxine hydrochloride (Pyridoxol; Vitamin 58-56-0 (hydrochloride) Metabolite; Enzyme/Protease; B6) is a pyridine derivative. Pyridoxine Keapl-Nrf2 NF-κB (Pyridoxol; Vitamin B6) exerts antioxidant effects in cell model of Alzheimer's disease via the Nrf-2/HO-1 pathway. HY-N0708 Vanillic acid Bacterial; Anti-infection; Vanillic acid is a flavoring agent found in edible 121-34-6 Endogenous Metabolic plants and fruits Vanillic acid inhibits NF-κB Metabolite; Enzyme/Protease; activation. Anti-inflammatory, antibacterial, and NF-κB NF-κB chemopreventive effects. HY-N0709 Coumarin Influenza Anti-infection Coumarin is the primary bioactive ingredient in 91-64-5 Virus Radix Glehniae, named Beishashen in China, which possesses many pharmacological activities, including anticancer, anti-inflamma- tion and antivirus activities. HY-N0711 Carvacrol Apoptosis; Anti-infection; Carvacrol is a monoterpenoid phenol isolated 499-75-2 Endogenous Apoptosis; from Lamiaceae family plants, with antioxidant, Metabolite; Metabolic anti-inflammatory and anticancer properties. Fungal; Notch Enzyme/Protease; Carvacrol causes cell cycle arrest in G0/G1, Neuronal downregulates Notch-1, and Jagged-1, and Signaling; Stem induces apoptosis. Cell/Wnt HY-N0717 L-Valine Endogenous Metabolic L-Valine is one of 20 proteinogenic amino acids. 72-18-4 Metabolite Enzyme/Protease L-Valine is an essential amino acid. HY-N0729 Linoleic acid Endogenous Metabolic Linoleic acid is a critical component of polyun- 60-33-3 Metabolite Enzyme/Protease saturated fatty acids. HY-N0756 Bornyl acetate Apoptosis Apoptosis Bornyl acetate is a potent odorant, exhibiting 76-49-3 one of the highest flavor dilution factor (FD factor). HY-N0771 L-Isoleucine Endogenous Metabolic L-isoleucine is a nonpolar hydrophobic amino 73-32-5 Metabolite Enzyme/Protease acid. L-Isoleucine is an essential amino acid. HY-N0830 Palmitic acid Endogenous Metabolic Palmitic acid is a long-chain saturated fatty acid 57-10-3 Metabolite Enzyme/Protease commonly found in both animals and plants. HY-N0832 L-Histidine Endogenous Metabolic L-Histidine is an essential amino acid for infants. 71-00-1 Metabolite; Enzyme/Protease L-Histidine is an inhibitor of mitochondrial Mitochondrial glutamine transport. Metabolism HY-N1096 Veratraldehyde Others Others Veratmldehyde is an important chemical used in 120-14-9 perfumery, agrochemical, and pharmaceutical industries. HY-N1132A D-(+)-Trehalose Others Others D-(+)-Trehalose dihydrate, isolated from 6138-23-4 dihydrate Saccharomyces cerevisiae, can be used as a food ingredient and pharmaceutical excipient. HY-N1390 Syringaldehyde COX Immunology/ Syringaldehyde is a polyphenolic compound 134-96-3 Inflammation belonging to the group of flavonoids and is found in different plant species like Manihot esculenta and Magnolia officinalis. Syringalde- hyde moderately inhibits COX-2 activity with an IC50 of 3.5 μg/mL. Anti-hyperglycemic and anti-inflammatory activities. HY-N1393 2-Methoxybenzoic Endogenous Metabolic 2-Methoxybenzoic acid (NSC 3778) is used as 579-75-9 acid Metabolite Enzyme/Protease an internal standard of salicylic acid and its putative biosynthetic precursors in cucumber leaves. Another known use is in the synthesis of Benextramine. HY-N1394 p-Anisic acid Bacterial; Anti-infection; p-Anisic acid (4-Methoxybenzoic acid) is one of 100-09-4 Endogenous Metabolic the isomers of anisic acid, with anti-bacterial and Metabolite Enzyme/Protease antiseptic properties. HY-N1406 6-Methylcoumarin Others Others 6-Methylcoumarin is a synthetic fragrance 92-48-8 widely used in cosmetics. HY-N1415 β-Caryophyllene Cannabinoid GPCR/G Protein; β-Caryophyllene is a CB2 receptor agonist. 87-44-5 Receptor; Metabolic Endogenous Enzyme/Protease Metabolite Neuronal Signaling HY-N1420 Rhamnose Endogenous Metabolic Rhamnose (L-Rhamnose) is a monosaccharide 3615-41-6 Metabolite Enzyme/Protease found in plants and bacteria. Rhamnose- conjugated immunogens is used in immuno- therapies. Rhamnose crosses the epithelia via the transcellular pathway and acts as a marker of intestinal absorption. HY-N1423 Glycocholic acid Bcl-2 Family; Apoptosis; Glycocholic acid is a bile acid with anticancer 475-31-0 Endogenous Metabolic activity, targeting against pump resistance- Metabolite Enzyme/Protease related and non-pump resistance-related pathways. HY-N1426 Raspberry ketone PPAR Cell Cycle/ Raspberry ketone is a major aromatic compound 5471-51-2 DNA Damage of red raspberry, widely used as a fragrance in cosmetics and as a flavoring agent in foodstuff; also shows PPAR-α agonistic activity. HY-N1428 Citric acid Antibiotic; Anti-infection; Citric acid is a weak organic tricarboxylic acid 77-92-9 Apoptosis; Apoptosis; found in citrus fruits. Citric acid is a natural Bacterial; Metabolic preservative and food tartness enhancer. Endogenous Enzyme/Protease Metabolite HY-N1428A 2-Hydroxy-1,2,3- propanetricarbo- xylic acid monohydrate HY-N1446 Oleic acid Apoptosis; Apoptosis; Oleic acid is an abundant monounsaturated fatty 112-80-1 Endogenous Membrane acid. Oleic acid is a Na+/K+ ATPase activator. Metabolite; Transporter/Ion Na+/K+ Channel; ATPase Metabolic Enzyme/Protease HY-N1500 Pulegone Endogenous Membrane Pulegone, the major chemical constituent of 89-82-7 Metabolite; Transporter/Ion Calamintha nepeta (L.) Savi essential oil which TRP Channel Channel; is an aromatic herb with a mint-oregano flavor, Metabolic is one of avian repellents. The molecular target Enzyme/Protease; for the repellent action of Pulegone in avian Neuronal species is nociceptive TRP ankyrin 1 (TRPA1). Signaling Pulegone stimulates both TRPM8 and TRPA1 channel in chicken sensory neurons and suppresses the former but not the latter at high concentrations. HY-N1925 Tea polyphenol Others Others Tea polyphenol is the floorboard of phenolic 84650-60-2 compounds in tea. Tea polyphenol exhibits biological activity including antioxidant and anti-cancer activities, inhibition of cell prolifera- tion, induction of apoptosis, cell cycle arrest and modulation of carcinogen metabolism. HY-N1926 Dihydrocoumarin Sirtuin Cell Cycle/ Dihydrocoumarin is a compound found in 119-84-6 DNA Damage; Melilotus officinalis. Dihydrocoumarin is a yeast Epigenetics Sir2p inhibitor. Dihydrocoumarin also inhibits human SIRT1 and SIRT2 with IC50s of 208 μM and 295 μM, respectively. HY-N1944 Nerolidol Bacterial; Anti-infection; Nerolidol is a natural membrane-active sesquiter- 7212-44-4 Endogenous Metabolic pene, with antitumor, antibacterial, antifungal Metabolite; Enzyme/Protease and antipamsitic activity. Fungal; Parasite HY-N2011 Octyl gallate Bacterial; Anti-infection; Octyl gallate (Progallin O) is widely used as a 1034-01-1 HSV; Influenza Immunology/ food additive, with antimicrobial and antioxidant Virus; Reactive Inflammation; activity. Octyl gallate (Progallin O) shows Oxygen Species Metabolic selective and sensitive fluorescent property. Enzyme/Protease; Octyl gallate shows a marked antiviral effect NF-κB against HSV-1, vesicular stomatitis virus (VSV) and poliovirus. HY-N2024 Maltose 69-79-4 HY-N2026 Propylparaben Bacterial; Anti-infection; Propylparaben is an antimicrobial agent, 94-13-3 Endogenous Metabolic preservative, flavouring agent. Metabolite Enzyme/Protease HY-N2041 Myristic acid Endogenous Metabolic Myristic acid is a saturated 14-carbon fatty acid 544-63-8 Metabolite Enzyme/Protease occurring in most animal and vegetable fats, particularly butterfat and coconut, palm, and nutmeg oils. HY-N2067 Vanillyl alcohol Apoptosis Apoptosis Vanillyl alcohol (p-(Hydroxymethyl)guaiacol), 498-00-0 derived from vanillin, is a phenolic alcohol and is used as a flavoring agent in foods and beverages. HY-N2071 Cedrol Cytochrome Anti-infection; Cedrol is a bioactive sesquiterpene, a potent 77-53-2 P450; Fungal Metabolic competitive inhibitor of cytochrome P-450 Enzyme/Protease (CYP) enzymes. Cedrol inhibits CYP2B6- mediated bupropion hydroxylase and CYP3A4- mediated midazolam hydroxylation with Ki of 0.9 μM and 3.4 μM, respectively. Cedrol also has weak inhibitory effect on CYP2C8, CYP2C9, and CYP2C19 enzymes. Cedrol is found in cedar essential oil and poetesses anti- septic, anti-inflammatory, anti-spasmodic, tonic, astringent, diuretic, sedative, insecticidal, and anti-fungal activities. HY-N2086 Ethyl palmitate 628-97-7 HY-N2195 Nootkatone Others Others Nootkatone, a neuroprotective agent from 4674-50-4 Alpiniae Oxyphyllae Fructus, has antioxidant and anti-inflammatory effects. Nootkatone improves cognitive impairment in lipopoly- saccharide-induced mouse model of Alzheimer's disease. HY-N2362 Alanine 302-72-7 HY-N3025 Zinc sulfate Others Others Zinc sulfate heptahydrate is a hydrate that is the 7446-20-0 (heptahydrate) heptahydrate form of zinc sulfate. Zinc sulfate heptahydrate is a dietary supplement used for zinc deficiency and to prevent the condition in those at high risk. HY-N3075 Phytol Bacterial; Anti-infection Phytol ((E)?-?Phytol), a diterpene alcohol from 150-86-7 Parasite chlorophyll widely used as a food additive and in medicinal fields, possesses promising anti- schistosomal properties. Phytol has antinocicep- tive and antioxidant activitiesas well as anti- inflammatory and antiallergic effects. Phytol has antimicrobial activity against Mycobacterium tuberculosis and Staphylococcus aureus. HY-N3544 Caryophyllene Endogenous Metabolic Caryophyllene oxide, isolated from from Annona 1139-30-6 oxide Metabolite Enzyme/Protease squamosa L. bark., possesses analgesic and anti- inflammatory activity. HY-N4100 Trilobatin HIV; SGLT Anti-infection; Trilobatin, a natural sweetener derived from? 4192-90-9 Membrane Lithocarpus polystachyus?Rehd, Trilobatin?is Transporter/Ion an HIV-1 entry inhibitor targeting the HIV-1 Channel Gp41 envelope. Neuroprotective effects. Trilobatin is also a SGLT1/2 inhibitor that selectively induces the proliferation of human hepatoblastoma cells. HY-N5132 (−)-Fenchone Others Others (−)-Fenchone, a bicyclic monoterpene, is widely 7787-20-4 distributed in plants and found in essential oils from Thuja occidentalis. (−)-Fenchone is oxi- dized to 6-endo-hydroxyfenchone, 6-exo- hydroxyfenchone and 10-hydroxyfenchone derivatives by CYP2A6 and CYP2B6 in human liver microsomes with CYP2A6 playing a more important role than CYP2B6. HY-N5142 α-Terpineol Bacterial Anti-infection α-Terpineol is isolated from Eucalyptus globulus 98-55-5 Labill, exhibits strong antimicrobial activity against periodontopathic and cariogenic bacteria. α-Terpineol possesses antifungal activity against T. mentagrophytes, and the activity might lead to irreversible cellular disruption. HY-N6056 Pentanoic acid 109-52-4 HY-N6655 DL-Methionine Others Others DL-methionine methylsulfonium chloride is a 3493-12-7 methylsulfonium naturally occurring methionine derivative. DL- (chloride) methionine methylsulfonium chloride protects gastric mucosal from ethanol-induced damage. HY-N6810 Thymol Bacterial Anti-infection Thymol is the main monoterpene phenol 89-83-8 occurring in essential oils isolated from plants belonging to the Lamiaceae family, and other plants such as those belonging to the Verbenaceae, Scrophulariaceae, Ranunculaceae and Apiaceae families. Thymol has antioxidant, anti-inflammatory, antibacterial and antifungal effects. HY-N6952 Geraniol Endogenous Anti-infection; Geraniol, an olefinic terpene, was found to 106-24-1 Metabolite; Metabolic inhibit growth of Candida albicans and Fungal Enzyme/Protease Saccharomyces cerevisiae strains. HY-N6996 Methyl Eugenol Others Others Methyl Eugenol, a phenylpropanoid chemical in 93-15-2 leaves, fruits, stems, and/or roots, may be released when that corresponding part of a plant is damaged as a result of feeding by an herbivore. Methyl Eugenol is used for male annihilation of the oriental fruit fly. HY-N7000 Perillyl alcohol Apoptosis; Apoptosis; Perillyl alcohol?is a monoterpene isolated from 536-59-4 Endogenous Metabolic the essential oils of lavendin, peppermint, Metabolite Enzyme/Protease spearmint, cherries, celery seeds, and several other plants. Perillyl alcohol?is active in inducing apoptosis in tumor cells without affecting normal cells. HY-N7063 Nerol Apoptosis; Anti-infection; Nerol is a constituent of neroli oil. Nerol Nerol 106-25-2 Endogenous Apoptosis; triggers mitochondrial dysfunction and induces Metabolite; Immunology/Infl apoptosis via elevation of Ca2+ and ROS. Fungal; ammation; Antifungal activity. Mitochondrial Metabolic Metabolism; Enzyme/Protease; Reactive NF-κB Oxygen Species HY-N7079 Erythorbic acid Others Others Erythorbic acid (D-Isoascothic acid), produced 89-65-6 from sugars derived from different sources, such as beets, sugar cane, and corn, is a food additive used predominantly in meats, poultry, and soft drinks. HY-N7079A Sodium erythorbate Others Others Sodium erythorbate (D-Isoascothic acid sodium), 6381-77-7 produced from sugars derived from different sources, such as beets, sugar cane, and corn, is a food additive used predominantly in meats, poultry, and soft drinks. HY-N7083 Citral Others Others Citral is a monoterpene found in Cymbopogon 5392-40-5 citratus essential oil, with antihyperalgesic, anti-nociceptive and anti-inflammatory effects. HY-N7090 Benzyl cinnamate HY-N7092 D-Fructose Others Others D-Fructose (D(−)-Fructose) is a naturally 57-48-7 occurring monosaccharide found in many plants. HY-N7117 1,4-Cineole Endogenous Membrane 1,4-Cineole is a widely distributed, natural, 470-67-7 Metabolite; Transporter/Ion oxygenated monoterpene. 1,4-Cineole, present TRP Channel Channel; in eucalyptus oil, activates both human TRPM8 Metabolic and human TRPA1. Enzyme/Protease; Neuronal Signaling HY-N7124 Benzyl acetate Others Others Benzyl acetate is a constituent of jasmin and of 140-11-4 the essential oils of ylang-ylang and neroli. Natural sources of Benzyl acetate include varieties of flowers like jasmine (Jasminum), and fruits like pear, apple. HY-N7393 Isomalt Lactate Metabolic Isomalt (Palatinitol), a well-tolerated, non-toxic 64519-82-0 Dehydrogenase Enzyme/Protease polyol and a protein-stabilizing excipient, stabilizes lactate dehydrogenase (LDH) moderately during freeze-drying, and performs better during storage. Isomalt is traditionally used as a sweetening agent in the food industry and as a tabletting excipient for pharmaceutical purposes. HY-P1645 Papain Cathepsin Metabolic Papain is a cysteine protease of the peptidase C1 9001-73-4 Enzyme/Protease family, which is used in food, pharmaceutical, textile, and cosmetic industries. HY-W001132 Indole Endogenous Metabolic Indole is an endogenous metabolite. 120-72-9 Metabolite Enzyme/Protease HY-W001245 4-Methylthiazole 693-95-8 HY-W002045 1-(4- 122-84-9 Methoxyphenyl)- propan-2-one HY-W002097 1-(5- 13679-74-8 Methylthiophen-2- yl)ethan-1-one HY-W004058 (Tetrahydrofuran-2- 97-99-4 yl)methanol HY-W004282 Undecanoic Endogenous Anti-infection; Undecanoic acid (Undecanoate) is a monocarbo- 112-37-8 acid Metabolite; Metabolic xylic acid with antimycotic property, which Fungal Enzyme/Protease inhibits the production of exocellular keratinase, lipase and the biosynthesis of several phospho- lipids in T. rubrum. HY-W004283 Pentadecanoic acid Endogenous Metabolic Pentadecylic acid is a saturated fatty acid with a 1002-84-2 Metabolite Enzyme/Protease 15-cathon backbone. HY-W004292 1-Undecanol 112-42-5 HY-W004298 10-Undecen-1-ol Others Others 10-Undecen-1-ol, converted from ricinoleic acid, 112-43-6 can be used as a comonomer for the introduction HY-W004842 Benzo [b]furan-2- of functional groups. 4265-16-1 carboxaldehyde HY-W004975 5- 13708-12-8 Methylquinoxaline HY-W005288 4-Vinylphenol 2628-17-3 HY-W005344 Ethyl 2-(2-methyl- 6413-10-1 1,3-dioxolan-2- yl)acetate HY-W005513 N,N-Bis(2- 120-40-1 hydroxyethyl)- dodecanamide HY-W006057 3-Methyl-2- Endogenous Metabolic 3-Methyl-2-oxobutanoic acid is a precursor of 759-05-7 oxobutanoic acid Metabolite Enzyme/Protease pantothenic acid in Escherichia coli. HY-W007355 Skatole Aryl Anti-infection; Skatole is produced by intestinal bacteria, 83-34-1 Hydrocarbon Autophagy; regulates intestinal epithelial cellular functions Receptor; Immunology/ through activating aryl hydrocarbon receptors Autophagy; Inflammation; and p38. Bacterial; MAPK/ERK Endogenous Pathway; Metabolite; Metabolic Fungal; p38 Enzyme/Protease MAPK HY-W007446 3-Phenylpropanal 104-53-0 HY-W007606 Tyramine Endogenous Metabolic Tyramine is an amino acid that helps regulate 51-67-2 Metabolite Enzyme/Protease blood pressure. Tyramine occurs naturally in the body, and it's found in certain foods. HY-W007617 Ethyl 3-oxo-3- 94-02-0 phenylpropanoate HY-W007692 Acetylpyrazine Others Others Acetylpyrazine (2-Acetylpyrazine) is fused to 22047-25-2 form many polycyclic compounds, as useful structures in pharmaceuticals and perfumes. Acetylpyrazine is a component of the folates (vitamin B compounds). HY-W007704 Methyl 4630-82-4 cyclohexanecar- boxylate HY-W007828 Methyl 3- 103-25-3 phenylpropanoate HY-W007888 2-Hydroxy-4- 698-27-1 methylbenzalde- hyde HY-W007926 2-Oxobutanoic Endogenous Metabolic 2-Oxobutanoic acid is a product in the 600-18-0 acid Metabolite Enzyme/Protease enzymatic cleavage of cystathionine. HY-W008270 2(5H)-Furanone 497-23-4 HY-W008591 2-Methoxypyridine 1628-89-3 HY-W009156 Hydroxycitric acid 6100-05-6 (tripotassium hydrate) HY-W009384 1,4-Dioxacyclohept- 105-95-3 adecane-5,17-dione HY-W009417 Cedryl acetate Glucosidase Metabolic Cedryl acetate is a tricyclic sesquiterpene 77-54-3 Enzyme/Protease isolated from the plant Psidium caudatum. Cedryl acetate shows α-glucosidase inhibitory activity. HY-W009516 Dibenzyl disulfide 150-60-7 HY-W009811 Tridecan-2-one 593-08-8 HY-W009948 Vanillin acetate Others Others Vanillin acetate is easily synthesized from 881-68-5 vanillin by treatment with acetic anhydride. HY-W010054 2- 93-18-5 Ethoxynaphthalene HY-W010141 1-(4- 645-13-6 Isopropylphenyl)- thanone HY-W010201 Citronellol Reactive Immunology/ Citronellol ((±)-Citronellol) is a monoterpene 106-22-9 Oxygen Inflammation; Pelargonium capitatum. Citronellol ((±)- Species Metabolic Citronellol) induces necroptosis of cancer cell Enzyme/Protease; via up-regulating TNF-α, RIP1/RIP3 activities, NF-κB down-regulating caspase-3/caspase-8 activities and increasing ROS (reactive oxygen species) accumulation. HY-W010293 Ethyl 4- 539-88-8 oxopentanoate HY-W010320 Ethyl maltol Others Others Ethyl maltol (2-Ethyl-3-hydroxy-4H-pyran-4- 4940-11-8 one), an odor-active (OA) compound, is an important food additive and the main component of a type of incense added to food. HY-W010392 Ethyl 2- 7452-79-1 methylbutanoate HY-W010435 Sulcatone 110-93-0 HY-W010476 2,3,5- 14667-55-1 Trimethylpyrazine HY-W010483 2-Phenylethylamine 64-04-0 HY-W010489 2-Phenylacetalde- Endogenous Metabolic 2-Phenylacetaldehyde is an endogenous 122-78-1 hyde Metabolite Enzyme/Protease metabolite. HY-W010531 trans-Hex-2-enoic 13419-69-7 acid HY-W010533A 2-Methyl-2- 3142-72-1 pentenoic acid HY-W010540 4,5- 3581-91-7 Dimethylthiazole HY-W010542 Azepan-2-one 105-60-2 HY-W010553 2,5-Dimethyl- Others Others 2,5-Dimethyl-3(2H)-furanone is a flavouring 14400-67-0 3(2H)-furanone substance without genotoxicity. HY-W010562 2-Methoxypyrazine HY-W010594 Tetrahydrothiophen- Endogenous Metabolic Tetrahydrothiophen-3-one is an endogenous 1003-04-9 3-one Metabolite Enzyme/Protease metabolite. HY-W010607 cis-3-Hexen-1-ol Others Others cis-3-Hexen-1-ol ((Z)-3-Hexen-1-ol) is a green 928-96-1 grassy smelling compound found in many fresh fruits and vegetables. cis-3-Hexen-1-ol is widely used as an added flavor in processed food to provide a fresh green quality. cis-3-Hexen-1-ol is an attractant to various insects. HY-W010611 3-Methylbut-2- Endogenous Metabolic 3-Methylbut-2-enoic acid is an endogenous 541-47-9 enoic acid Metabolite Enzyme/Protease metabolite. HY-W010627 2,5-Dimethyl-1H- 14400-67-0 pyrrole HY-W010970 5′-Guanylic acid Endogenous Metabolic 5′-Guanylic acid disodium salt (5′-GMP 5550-12-9 (disodium salt) Metabolite Enzyme/Protease disodium salt) is composed of guanine, ribose, and phosphate moieties and it is a nucleotide monomer in messenger RNA. Guanosine derivatives are involved in intracellular signal transduction and have been identified in repetitive genomic sequences in telomeres, in ribosomal DNA, immunoglobulin heavy-chain switch regions, and in the control regions of proto-oncogenes. HY-W011053 Neotame 165450-17-9 HY-W011678 Octadecan-1-amine 124-30-1 HY-W012499 N-Acetyl-L- Endogenous Metabolic N-Acetyl-L-methionine, a human metabolite, is 65-82-7 methionine Metabolite Enzyme/Protease nutritionally and metabolically equivalent to L- methionine. L-methionine is an indispensable amino acid required for normal growth and development. HY-W012530 2-Oxo-3- Endogenous Metabolic 2-Oxo-3-phenylpropanoic acid is used in the 156-06-9 phenylpropanoic Metabolite Enzyme/Protease synthesis of 3-phenyllactic acid (PLA) by acid lactate dehydrogenase. HY-W012556 Ethyl 3- 2305-25-1 hydroxyhexanoate HY-W012575 2,4- Endogenous Metabolic 2,4-Dihydroxybenzoic acid is a degradation 89-86-1 Dihydroxybenzoic Metabolite Enzyme/Protease product of cyaniding glycoside from tart acid cheeries in cell culture. HY-W012595 Benzylideneace tone 122-57-6 HY-W012634 Benzo[d]thiazole 95-16-9 HY-W012653 4′- 122-00-9 Methylacetophen- one HY-W012657 4- 4748-78-1 Ethylbenzaldehyde HY-W012658 2- Endogenous Metabolic 2-Methylacetophenone is an endogenous 577-16-2 Methylacetophen- Metabolite Enzyme/Protease metabolite. one HY-W012701 Ethyl 3- 5405-41-4 hydroxybutyrate HY-W012722 4-Methyl-2- Endogenous Metabolic 4-Methyl-2-oxopentanoic acid, an abnormal 816-66-0 oxopentanoic acid Metabolite Enzyme/Protease metabolite, is both a neurotoxin and a metabotoxin. HY-W012732 Isoquinoline HY-W012788 Maltol Endogenous Metabolic Maltol, a type of aromatic compound, exists in 118-71-8 Metabolite Enzyme/Protease high concentrations in red ginseng. Maltol is a potent antioxidative agent and typically is used to enhance flavor and preserve food. HY-W012813 1-(5-Methylfuran- 1193-79-9 2-yl)ethanone HY-W012836 4-Ethylphenol Endogenous Metabolic 4-Ethylphenol is a volatile phenolic compound 123-07-9 Metabolite Enzyme/Protease associated with off-odour in wine. HY-W012889 DL-Valine 516-06-3 HY-W012956 1-(1H-Pyrrol-2- 1072-83-9 yl)ethanone HY-W012980 3-Methylbutanoic Endogenous Metabolic 3-Methylbutanoic acid is a natural fatty acid and 503-74-2 acid Metabolite Enzyme/Protease known to effect on neonatal death and possible Jamaican vomiting sickness in human. HY-W012995 5-Hexen-1-ol 821-41-0 HY-W012999 Tiglic acid Endogenous Metabolic Tiglic acid is a monocarboxylic unsaturated 80-59-1 Metabolite Enzyme/Protease organic acid found in croton oil and in several other natural products. Tiglic aci has a role as a plant metabolite. HY-W013014 3-Methyl-2- Endogenous Metabolic 3-Methyl-2-cyclopenten-1-one is an endogenous 2758-18-1 cyclopenten-1-one Metabolite Enzyme/Protease metabolite. HY-W013035 3-Methyl-2-buten- Endogenous Metabolic 3-Methyl-2-buten-1-ol is an endogenous 556-82-1 1-ol Metabolite Enzyme/Protease metabolite. HY-W013040 Pyrazine 290-37-9 HY-W013573 S-Allyl-L- Apoptosis Apoptosis S-Allyl-L-cysteine, one of the organosulfur 21593-77-1 cysteine compounds found in AGE, possess various biological effects including neurotrophic activity, anti-cancer activity, anti-inflammatory activity. HY-W013627 (2E,4E)-Deca-2,4- 25152-84-5 dienal HY-W013636 2-Ketoglutaric acid Endogenous Metabolic 2-Ketoglutaric acid (Alpha-Ketoglutaric acid) 328-50-7 Metabolite; Enzyme/Protease is an intermediate in the production of ATP or Tyrosinase GTP in the Krebs cycle. 2-Ketoglutaric acid also acts as the major carbon skeleton for nitrogen-assimilatory reactions. 2-Ketoglutaric acid is a reversible inhibitor of tyrosinase (IC50 = 15 mM). HY-W013807 Dibutyl sebacate Others Others Dibutyl sebacate (Dibutyl decanedioate) is a 109-43-3 dibutyl ester of sebacic acid, mainly used as a plasticizer in production of plastics. HY-W014102 L-Alanyl-L- Endogenous Metabolic L-Alanyl-L-glutamine, a glutamine dipeptide, is 39537-23-0 glutamine Metabolite Enzyme/Protease benefit for the antioxidant system, attenuating inflammation, and may modulate the heat shock protein (HSP) response in catabolic situations. HY-W014207 Ethyl undecanoate 627-90-7 HY-W014325 TRPM8 antagonist TRP Channel Membrane TRPM8 antagonist WS-3 is an agonist of 39711-79-0 WS-3 Transporter/Ion TRPM8 with an EC50 of 3.7 μM. Channel; Neuronal Signaling HY-W014388 1,3- 102-04-5 Diphenylpropan-2- one HY-W015301 Dimethyl adipate 627-93-0 HY-W015309 Decanoic acid Endogenous Metabolic Decanoic acid belongs to the class of organic 334-48-5 Metabolite Enzyme/Protease compounds known as medium-chain fatty acids. HY-W015342 Methyl anisate 121-98-2 HY-W015371 Ethyl phenylacetate 101-97-3 HY-W015410 Disodium succinate Others Others Disodium succinate is the?disodium?salt of'? 150-90-3 Succinic acid. Succinic acid is an intermediate product of the tricarboxylic acid cycle, as well as one of fermentation products of anaerobic metabolism. HY-W015611 L-(+)- Endogenous Metabolic L-(+)-Arabinose selectively inhibits intestinal 5328-37-0 Arabinose Metabolite Enzyme/Protease sucrase activity in a noncompetitive manner and suppresses the plasma glucose increase due to sucrose ingestion. HY-W015618 2′,4′- 89-74-7 Dimethylacetophen- one HY-W015695 4-Methyl-5- 137-00-8 thiazoleethanol HY-W015709 Ethyl hex-3-enoate 2396-83-0 HY-W015777 (4-Methoxyphenyl)- 105-13-5 methanol HY-W015780 1,4- 150-78-7 Dimethoxybenzene HY-W015786 4-Ethoxyphenol 622-62-8 HY-W015820 Isobenzofuran- 87-41-2 1(3H)-one HY-W015861 p-Tolylmethanol 589-18-4 HY-W015883 Fumaric acid Endogenous Metabolic Fumaric acid, associated with fumarase 110-17-8 Metabolite Enzyme/Protease deficiency, is identified as an oncometabolite or an endogenous, cancer causing metabolite. HY-W016081 Allyl cinnamate 1866-31-5 HY-W016089 Ethyl 2-(2,4- 6290-17-1 dimethyl-1,3- dioxolan-2- ypacetate HY-W016319 (S)-2- 138-15-8 aminopentanedioic acid hydrochloride HY-W016610 2-Ethoxy-5- 94-86-0 propenylphenol HY-W016806 Sodium 4- (methoxycarbonyl) phenolate HY-W016976 Allyl heptanoate 142-19-8 HY-W017018 L-Ornithine Endogenous Metabolic L-Ornithine hydrochloride is a free amino acid 3184-13-2 (hydrochloride) Metabolite Enzyme/Protease that plays a central role in the urea cycle and is also important for the disposal of excess nitrogen. HY-W017077 4-Methylbiphenyl Endogenous Metabolic 4-Methylbiphenyl is an endogenous metabolite. 644-08-6 Metabolite Enzyme/Protease HY-W017140 2-(sec-Buty1)-3- 24168-70-5 methoxypyrazine HY-W017141 2-Isobutyl-3- 24683-00-9 methoxypyrazine HY-W017212 Methyl cinnamate AMPK; Anti-infection; Methyl cinnamate (Methyl 3-phenylpropenoate), 103-26-4 Bacterial; Epigenetics; an active component of Zanthoxylum armatum, Tyrosinase Metabolic is a widely used natural flavor compound. Enzyme/Protease; Methyl cinnamate (Methyl 3-phenylpropenoate) PI3K/Akt/mTOR possesses antimicrobial activity and is a tyro- sinase inhibitor that can prevent food browning. Methyl cinnamate (Methyl 3-phenylpropenoate) has antiadipogenic activity through mechanisms mediated, in part, by the CaMKK2-AMPK signaling pathway. HY-W017232 6- 5263-87-6 Methoxyquinoline HY-W017278 2-((Isopropylthio)- 1883-78-9 methyl)furan HY-W017316 Terpinen-4-ol Endogenous Metabolic Terpinen-4-ol (4-Carvomenthenol), a naturally 562-74-3 Metabolite Enzyme/Protease occurring monoterpene, is the main bioactive component of tea-tree oil. Terpinen-4-ol suppresses inflammatory mediator production by activated human monocytes. Terpinen-4-ol significantly enhances the effect of several chemotherapeutic and biological agents. HY-W017370 Carveol 99-48-9 HY-W017371 p-Dithiane-2,5-diol 40018-26-6 HY-W017374 4-Ethy1-2- 2785-89-9 methoxyphenol HY-W017428 4-Ethoxybenzalde- 10031-82-0 hyde HY-W017522 Adipic acid Endogenous Metabolic Adipic acid is found to be associated with HMG- 124-04-9 Metabolite Enzyme/Protease CoA lyase deficiency, carnitine-acylcarnitine translocase deficiency, malonyl-CoA decarboxy- lase deficiency, and medium Chain acyl-CoA dehydrogenase deficiency, which are inborn errors of metabolism. HY-W017562 5- 104-50-7 Butyldihydrofuran- 2(3H)-one HY-W017592 2- 1073-29-6 (Methylthio)phenol HY-W017611 4-Propylphenol 645-56-7 HY-W017613 (Ethoxymethyl)- 539-30-0 benzene HY-W018501 Methyl p-tert- 3549-23-3 butylphenylacetate HY-W018653 Cyclohexaneacetic 5292-21-7 acid HY-W018758 1-Phenylpropane- Others Others 1-Phenylpropane-1,2-dione, isolated from young 579-07-7 1,2-dione Ephedra sinica Stapf (Ephedraceae), is bio- synthetic precursors of the ephedrine alkaloids. HY-W018772 D-Ribose(mixture Endogenous Metabolic D-Ribose(mixture of isomers) is an energy 50-69-1 of isomers) Metabolite Enzyme/Protease enhancer, and acts as a sugar moiety of ATP, and widely used as a metabolic therapy supple- ment for chronic fatigue syndrome or cardiac energy metabolism. D-Ribose(mixture of isomers) is active in protein glycation, induces NF-κB inflammation in a RAGE-dependent manner. HY-W019711 trans- Endogenous Metabolic trans-Cinnamaldehyde can be used to prepare 14371-10-9 Cinnamaldehyde Metabolite Enzyme/Protease highly polyfunctionalized furan ring by reaction of alkyl isocyanides with dialkyl acetylenedi- calboxylate. trans-Cinnamaldehyde can be used to synthesize trans-cinnamaldehyde-β- cyclodextrin complex, an antimicrobial edible coating that increases the shelf life of fresh-cut fruits. HY-W019894 Manganese 7773-01-5 dichloride HY-W019901 Anhydrous 7778-18-9 calcium sulfate HY-W020014 Pyruvic aldehyde 78-98-8 HY-W026742 Ethyl anthranilate 87-25-2 HY-W027751 2-Methylanisole 578-58-5 HY-W027872 Piperonyl acetone 55418-52-5 HY-W032013 1-Octanol Calcium Membrane 1-Octanol (Octanol), a saturated fatty alcohol, is 111-87-5 Channel; Transporter/Ion a T-type calcium channels (T-channels) inhibitor Endogenous Channel; with an IC50 of 4 μM for native T- currents. Metabolite Metabolic 1-Octanol is a highly attractive biofuel with Enzyme/Protease; diesel-like properties. Neuronal Signaling HY-W035362 Cyclopentadecano- 106-02-5 lide HY-W038287 2- 95-21-6 Methylbenzoxazole HY-W039157 2-Acetyl-3- 32974-92-8 ethylpyrazine HY-W039718 1-(2,4- 38205-60-6 Dimethylthiazol- 5-yl)ethan-1-one HY-W040226 Indigo carmine Others Others Indigo carmine is an efficient reagent for the 860-22-0 determination of ozone by chemlluminescence (CL). HY-W040240 (35,4R,5S)- Endogenous Metabolic (3S,4R,5S)-1,3,4,5,6-Pentahydroxyhexan-2- 87-79-6 1,3,4,5,6- Metabolite Enzyme/Protease one is an endogenous metabolite. Pentahydroxyhexan- 2-one HY-W040790 2,6- 108-50-9 Dimethylpyrazine HY-W040948 2-Ethylpyrazine 13925-00-3 HY-W040971 Creosol Endogenous Metabolic Creosol is an endogenous metabolite. 93-51-6 Metabolite Enzyme/Protease HY-W041301 4,4,7a-Trimethyl- 15356-74-8 5,6,7,7a- tetrahydrobenzo furan-2(4H)-one HY-W041470 4-Methyl-l-phenyl- 5349-62-2 2-pentanone HY-W041533 5,6,7,8- 34413-35-9 Tetrahydroquinoxa- line HY-W041912 Ethyl 2- 620-80-4 benzylidene-3- oxobutanoate HY-W052009 Methyl 2- hydroxyethyl cellulose HY-W067358 2-Methylpyrazine 109-08-0 HY-W067695 Octahydro-2H- 4430-31-3 chromen-2-one HY-W086991 3-Methyl-2- 1193-18-6 cyclohexenone HY-W087045 Benzyl formate 104-57-4 HY-W087922 Tridodecylamine 102-87-4 HY-W087943 Methyl octanoate 111-11-5 HY-W087984 Heptane-1-thiol 1639-09-4 HY-W087985 Isopentyl 2050-01-3 isobutyrate HY-W087987 2-Pentylthiophene 4861-58-9 HY-W088065 Sodium formate 141-53-7 HY-W088319 Butyramide 541-35-5 HY-W088425 Methyl 3- 13532-18-8 (methylthio)propan- oate HY-W088436 1-(1-Methyl-1H- 932-16-1 pyrrol-2-yl)ethan-1- one HY-Y0016 Rhodamine B Others Others Rhodamine B is a staining fluorescent dye, 81-88-9 commonly used for dyeing textiles, paper, soap, leather, and drugs. HY-Y0035 4,4-Dimethoxy-2- 5436-21-5 butanone HY-Y0045 2-Acetylthiazole 24295-03-2 HY-Y0073 4- HBV Anti-infection 4-Hydroxyacetophenone (P-hydroxyaceto- 99-93-4 Hydroxyacetophen phenone) is a key hepatoprotective and one choleretic compound in Artemisia capillaris and A. morrisonensis, also has an anti-hepatitis B virus effect and anti-inflammatory effect. HY-Y0078 Cinnamyl Alcohol PPAR Cell Cycle/DNA Cinnamyl Alcohol is an active component from 104-54-1 Damage chestnut flower, inhibits increased PPARγ expression, with anti-obesity activity. HY-Y0110 2-Naphthol Endogenous Metabolic 2-Naphthol is a metabolite of naphthalene, 135-19-3 Metabolite Enzyme/Protease catalyzed by cytochrome P450 (CYP) isozymes (CYP 1A1, CYP 1A2, CYP 2A1, CYP 2E1 and CYP 2F2). HY-Y0121 SemaSORB 9827 103-36-6 HY-Y0172 Butylated Ferroptosis Apoptosis Butylated hydroxytoluene is an antioxidant 128-37-0 hydroxytoluene widely used in foods and in food-related products. Butylated hydroxytoluene is a Ferroptosis inhibitor. HY-Y0189 Methyl Salicylate COX Immunology/ Methyl Salicylate (Wintergreen oil) is a topical 119-36-8 Inflammation analgesic and anti-inflammatory agent. Also used as a pesticide, a denaturant, a fragrance ingredient, and a flavoring agent in food and tobacco products. A systemic acquired resistance (SAR) signal in tobacco. A topical nonsteroidal anti-inflammatory drug (NSAID). Methyl salicylate lactoside is a COX inhibitor. HY-Y0190 (2R,3R)-Diethyl 87-91-2 2,3- dihydroxysuccinate HY-Y0248A Farnesol Antibiotic; Anti-infection; Farnesol is a sesquiterpene alcohol that modulates 4602-84-0 Bacterial; Metabolic cell-to-cell communication in Candida albicans, Endogenous Enzyme/Protease and has the activity in inhibiting bacteria. Metabolite HY-Y0252 L-Proline Endogenous Metabolic L-Proline is one of the twenty amino acids used 147-85-3 Metabolite Enzyme/Protease in living organisms as the building blocks of proteins. HY-Y0264 4-Hydroxybenzoic Bacterial; Anti-infection; 4-Hydroxybenzoic acid, a phenolic derivative of 99-96-7 acid Endogenous Metabolic benzoic acid, could inhibit most gram-positive Metabolite Enzyme/Protease and some gram-negative bacteria, with an IC50 of 160 μg/mL. HY-Y0267 Phenoxyacetic acid Endogenous Metabolic Phenoxyacetic acid is an endogenous metabolite. 122-59-8 Metabolite Enzyme/Protease HY-Y0271 Urea Endogenous Metabolic Urea is a powerful protein denaturant via both 57-13-6 Metabolite Enzyme/Protease direct and indirect mechanisms. A potent emollient and keratolytic agent. Used as a diuretic agent. Blood urea nitrogen (BUN) has been utilized to evaluate renal function. Widely used in fertilizers as a source of nitrogen and is an important raw material for the chemical industry. HY-Y0272 Saccharin Bacterial Anti-infection Saccharin is an orally active, non-caloric 81-07-2 artificial sweeteners (NAS). Saccharin has bacteriostatic and microbiome-modulating properties. HY-Y0283 Antistrumin 7681-114 HY-Y0284 Diethyl phthalate HY-Y0287 Carbonate (calcium) 471-34-1 HY-Y0289 1-Dodecanol 112-53-8 HY-Y0293 L-Tartaric acid Endogenous Metabolic L-Tartaric acid (L-(+)-Tartaric acid) is an endo- 87-69-4 Metabolite Enzyme/Protease genous metabolite. HY-Y0308 Hydrogen 7558-79-4 disodium phosphate HY-Y0313 p- Endogenous Membrane p-Hydroxybenzaldehyde is a one of the major 123-08-0 Hydroxybenzalde- Metabolite; Transporter/Ion components in Dendrocalamus asper bamboo hyde GABA Channel; shoots, with antagonistic effect on GABAA Receptor Metabolic receptor of the α1β2γ2S subtype at high Enzyme/Protease; concentrations. Neuronal Signaling HY-Y0316 Sodium dodecyl 151-21-3 sulfate HY-Y0319B Acetic acid 127-08-2 (potassium) HY-Y0337 L-Cysteine Endogenous Apoptosis; L-Cysteine is a thiol-containing non-essential 52-90-4 Metabolite; Metabolic amino acid that is oxidized to form cystine. Ferroptosis Enzyme/Protease HY-Y0337A L-Cysteine Endogenous Metabolic L-Cysteine hydrochloride is a conditionally 52-89-1 (hydrochloride) Metabolite Enzyme/Protease essential amino acid, which acts as a precursor for biologically active molecules such as hydrogen sulphide (H2S), glutathione and taurine. L-Cysteine hydrochloride suppresses ghrelin and reduces appetite in rodents and humans. HY-Y0344 Sodium chloride 7647-14-5 HY-Y0366 Lauric acid Bacterial; Anti-infection; Lauric acid is a middle chain-free fatty acid with 143-07-7 Endogenous Metabolic strong bactericidal properties. The EC50s for P. Metabolite Enzyme/Protease acnes, S. aureus, S. epidermidis, are 2, 6, 4 μg/ mL, respectively. HY-Y0367 Maleic Acid Bacterial; Anti-infection; Maleic Acid is a Glutamate Decarboxylase 110-16-7 Endogenous Metabolic (GAD) inhibitor of E. coli and L. monocytogenes. Metabolite Enzyme/Protease HY-Y0479 L-Lactic acid Antibiotic; Anti-infection; L-Lactic acid is a buildiing block which can be 79-33-4 Bacterial; Metabolic used as a precursor for the production of the Endogenous Enzyme/Protease bioplastic polymer poly-lactic acid. Metabolite HY-Y0481A Stannous dichloride (dihydrate) HY-Y0498 Aluminum oxide HY-Y0537 Potassium chloride 7447-40-7 HY-Y0543 5-Methylfurfural Others Others 5-Methylfurfural is a naturally occurring 620-02-0 substance, found in cigarette smoke condensate, licorice essential oil, stored dehydrated orange powder, baked potato flour, volatile compounds of roast beef, aroma concentrate of sponge cake, bread and in coffee, tea and cocoa. A flavoring agent. HY-Y0546 Benzophenone 119-61-9 HY-Y0569 D-Gluconic acid Endogenous Metabolic D-Gluconic acid is the carboxylic acid by the 526-95-4 Metabolite Enzyme/Protease oxidation with antiseptic and chelating properties. HY-Y0600 Thioanisole 100-68-5 HY-Y0624 4-Pentenoic acid 591-80-0 HY-Y0682 Ethylenediamin etetraacetic acid HY-Y0682A Ethylenediamin 6381-92-6 etetraacetic acid disodium salt dihydrate HY-Y0703 Sodium Others Others Sodium carboxymethyl cellulose (Viscosity:800- 9004-32-4 carboxymethyl 1200 mPa.s) is the sodium salt of cellulose cellulose arboxymethyl and frequently used as viscous (Viscosity:800- agent, paste and barrier agent. 1200 mPa.s) HY-Y0708 Calcium hydrogen phosphate dihydrate HY-Y0740 4- Endogenous Metabolic 4-Methoxybenzaldehyde is a naturally occurring 123-11-5 Methoxybenzalde- Metabolite Enzyme/Protease fragrant phenolic compound that is soluble in hyde acetone. 4-Methoxybenzaldehyde has been found in many plant species including horseradish, anise, star anise. 4-Methoxybenz- aldehyde is a possible neurotoxicant and it has shown effects that include mortality, attractancy, and interference with host seeking. HY-Y0743 1-(Pyridin-2- 1122-62-9 yl)ethan-l-one HY-Y0751 1-(Pyridin-3- 350-03-8 yl)ethanone HY-Y0756 Carbonic acid 144-55-8 monosodium salt HY-Y0760 3-Methoxybenzoic Endogenous Metabolic 3-Methoxybenzoic acid can be used in the 586-38-9 acid Metabolite Enzyme/Protease synthesis of 3-methoxybenzoates of europium (III) and gadolinium (III). HY-Y0781 Pyruvic acid Endogenous Metabolic Pyruvic acid is an intermediate metabolite in the 127-17-3 Metabolite Enzyme/Protease metabolism of carbohydrates, proteins, and fats. HY-Y0790 Cuminaldehyde Endogenous Metabolic Cuminaldehyde is the major component of 122-03-2 Metabolite Enzyme/Protease Cuminum cyminum, a natural aldehyde with inhibitory effect on alpha-synuclein fibrillation and cytotoxicity. Cuminaldehyde shows anti- cancer activity. HY-Y0808 Dimethyl succinate 106-65-0 HY-Y0813 Iron 7439-89-6 HY-Y0836 Diethyl succinate Others Others Diethyl succinate (Diethyl Butanedioate) is used 123-25-1 at physiological pH and crosses biological membranes, incorporates into cells in tissue culture and is metabolized by the TCA cycle. Diethyl succinate is known to be non-toxic and used in fragrances and flavoring. HY-Y0839 Levulinic acid Endogenous Metabolic Levulinic acid is a precursor for the synthesis of 123-76-2 Metabolite Enzyme/Protease biofuels, such as ethyl levulinate. HY-Y0873 PEG300 Others Others PEG300 (Polyethylene glycol 300), a neutral 25322-68-3 polymer of molecular weight 300, is a water- soluble, low immunogenic and biocompatible polymer formed by repeating units of ethylene glycol. HY-Y0892 4-Hydroxybenzyl Apoptosis; Apoptosis; 4-Hydroxybenzyl alcohol is a phenolic 623-05-2 alcohol Endogenous Metabolic compound widely distributed in various kinds of Metabolite Enzyme/Protease plants. Anti-inflammatory, anti-oxidant, anti- nociceptive activity. Neuroprotective effect. Inhibitor of tumor angiogenesis and growth. HY-Y0921 (±)-1,2- Others Others (±)-1,2-Propanediol is an aliphatic alcohol and 57-55-6 Propanediol frequently used as an excipient in many drug formulations to increase the solubility and stability of drugs. HY-Y0932 Isophorone 78-59-1 HY-Y0946 Acetamide Endogenous Metabolic Acetamide is used primarily as a solvent and a 60-35-5 Metabolite Enzyme/Protease plasticizer. HY-Y0949 Methyl 2- Endogenous Metabolic Methyl 2-furoate (Methyl furan-2-carboxylate) is 611-13-2 furoate Metabolite Enzyme/Protease a building block in chemical synthesis. A flavoring agent in food. Found in cranberries, guava fruits, raisins and other fruits. Also present in baked potato, roasted filberts, roasted peanut, tomatoes, coffee, cocoa, okra, etc. HY-Y0961 Copper(I) iodide 7681-65-4 HY-Y0966 Glycine Endogenous Membrane Glycine is an inhibitory neurotransmitter in the 56-40-6 Metabolite; Transporter/Ion CNS and also acts as a co-agonist along with iGluR Channel; glutamate, facilitating an excitatory potential at Metabolic the glutaminergic N-methyl-D-aspartic acid Enzyme/Protease; (NMDA) receptors. Neuronal Signaling HY-Y0989 Acetophenone 98-86-2 HY-Y1011 2-Ethylhexan-1-ol 104-76-7 HY-Y1069 (S)-2- Endogenous Metabolic (S)-2-Hydroxysuccinic acid is a dicalboxylic 97-67-6 Hydroxysuccinic Metabolite Enzyme/Protease acid in naturally occurring form, contributes to acid the pleasantly sour taste of fruits and is used as a food additive. HY-Y1088 Hydrocinnamic Endogenous Metabolic Hydrocinnamic acid is the major rhizospheric 501-52-0 acid Metabolite Enzyme/Protease compound with known growth regulatory HY-Y1093 Ethyl acetoacetate activities. 141-97-9 HY-Y1103 Iron(II) sulfate 7782-63-0 heptahydrate HY-Y1116 Magnesium oxide 1309-48-4 HY-Y1177 Diphenyl disulfide 882-33-7 HY-Y1220 Dipotassium 584-08-7 carbonate HY-Y1311 Malic acid Endogenous Metabolic Malic acid is a dicarboxylic acid that is naturally 6915-15-7 Metabolite Enzyme/Protease found in fruits such as apples and pears. It plays a role in many sour or tart foods. HY-Y1316 Sodium benzoate 532-32-1 HY-Y1362 Ethyl pyruvate 617-35-6 HY-Y1366 Hydroxyacetone 116-09-6 HY-Y1373 Cyclohexanecar- Endogenous Metabolic Cyclohexanecarboxylic acid is a Valproate 98-89-5 boxylic acid Metabolite Enzyme/Protease structural analogue with anticonvulsant action. HY-Y1426 2′- Others Others 2′-Hydroxyacetophenone is found in alcoholic 118-93-4 Hydroxyacetophen- beverages. 2′-Hydroxyacetophenone is present one in tomato, cassia, fried beef, rum, whiskey, cocoa, coffee and black tea. 2′-Hydroxyaceto- phenone is a flavouring ingredient. Building block in chemical synthesis. HY-Y1673 Potassium bromide 7758-02-3 HY-Y1683 DL-Menthol GABA Membrane DL-Menthol is a relative configuration of (−)- 89-78-1 Receptor Transporter/Ion Menthol. DL-Menthol induces surgical Channel; GABAA receptor. anesthesia for fish that relates to the activation of Neuronal Signaling HY-Y1718 NSC 25955 Endogenous Metabolic NSC 25955 is an endogenous metabolite. 638-53-9 Metabolite Enzyme/Protease HY-Y1809 1- Endogenous Metabolic 1-Hydroxyoctadecane is an endogenous metabolite. 112-92-5 Hydroxyoctadecane Metabolite Enzyme/Protease HY-Y1829 Hydratropaldehyde 93-53-8 HY-Y1878 Copper sulfate 7758-98-7 HY-Y1879 Manganese 7785-87-7 sulfate HY-Y1880 Carbonic acid sodium salt, hydrate HY-Y1883 Hydrol SW 9002-93-1 HY-Y1885 Tetrasodium 7722-88-5 pyrophosphate HY-Y1888 Corn oil Others Others Corn oil, extracted from the germ of corn, 8001-30-7 can be used as a carrier for drug molecules. HY-Y1890 Cremophor EL Others Others Cremophor EL is a polyethoxylated surfactant. 61791-12-6 HY-Y1891 Tween 80 Others Others Tween 80 is a surfactant which can also reduce 9005-65-6 bacterial attachment and inhibit biofilm formation. HY-Y1892 Gelucire 44/14 Others Others Gelucire 44/14 is a potential and safe absorption 121548-04-7 enhancer for improving the absorption of poorly a bsorbable drugs including insulin and calcitonin by pulmonary delivery. HY-Z0041 Benzaldehyde 1125-88-8 dimethyl acetal HY-Z0453 Methyl 2- 606-45-1 methoxybenzoate HY-Z0478 (−)-Limonene Others Others (−)-Limonene ((S)-(−)-Limonene) is a monoter- 5989-54-8 pene found in many pine-needle oils and in turpentine. (−)-Limonene can induce a mild bronchoconstrictive effect. TCG0275 Copper (II) 527-09-3 Gluconate

Additional information about the additional ingredients listed in Table 1 (e.g., the ingredient's target, pathway, and/or biological activity) can be determined from publicly available databases and websites. As an example, the American Chemical Society's website (see, the World Wide Web at cas.org), the Chemical Book (at the World Wide Web chemicalbook.com), and/or Med Chem Express (see, the World Wide Web at medchemexpress.com) provide relevant information for the additional ingredients; this information can be obtained by searching the website using an ingredient's name or CAS number. The contents of these websites, with respect to the additional ingredients listed in Table 1, are incorporated by references in their entireties.

Compositions of the present disclosure are formulated to be suitable for in vivo administration to a mammal. Such compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration. Pharmaceutical excipients can be aqueous liquids, such as water or saline. Pharmaceutical excipients can be lipid based, e.g., comprising a liquid or solid oil. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. The pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when any composition described herein is administered parentally or in some oral formulations. In embodiments, the compositions described herein are suspended in a saline buffer (including, without limitation Ringer's, TBS, PBS, HEPES, HBSS, and the like). Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, glycerol monostearate, mannitol, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Any composition described herein, if desired, can also comprise pH buffering agents.

In embodiments, the compositions of the present disclosure are formulated for oral administration, for injection, or for topical administration. Administering the composition may comprise intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.

The compositions suitable for parenteral administration (e.g., intravenous injection or infusion, intraarterial injection or infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, and intra-arterial injection or infusion) include, for example, solutions, suspensions, dispersions, emulsions, and the like, or in another acceptable format used in methods well known in the art.

Compositions suitable for enteral administration (e.g., oral administration) may be formulated as a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge, a pill, or a capsule, or in another acceptable format used in methods well known in the art.

In some embodiments, the active ingredient (disulfiram) and the potentiating ingredient (cinnamaldehyde) are formulated into a single composition, e.g., for oral administration. In some cases, disulfiram and cinnamaldehyde are combined into a single tablet or pill during manufacturing of the tablet or pill or by a compounding company/laboratory. Alternately, disulfiram and cinnamaldehyde are combined into a single capsule by combining the contents of capsules containing disulfiram and capsules containing cinnamaldehyde. Additionally, powders or pellets of disulfiram and cinnamaldehyde may be otherwise obtained and compounded into pills/tablets or combined into capsules.

As described above, a composition of the present disclosure may further comprise one or more additional ingredients (e.g., from Table 1). The one or more additional ingredients may be formulated into the single tablet, pill, or capsule with disulfiram and cinnamaldehyde.

In other embodiments, the active ingredient that is disulfiram and potentiating ingredient that is cinnamaldehyde are formulated into distinct compositions, e.g., for oral administration. In some cases, disulfiram is present in a single tablet, pill, or capsule and the cinnamaldehyde is present in another tablet, pill, or capsule. Further, a third composition, tablet, pill, or capsule may include one or more additional ingredients (e.g., from Table 1).

When the composition is for oral administration and is in solid form (e.g., a pill, tablet, or capsule), the composition may comprise delay-release components. For example, a pill, tablet, or capsule may comprise a coating that slows release of the agents and/or prevents release of disulfiram and/or the one or more additional ingredients until the pill, tablet, or capsule has arrived at a desired location of the mammal's digestive system.

Compositions suitable for topical administration can be formulated in a solution, gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, aerosol, patch, or the like in a pharmaceutically or cosmetically acceptable format used in methods well known in the art.

Compositions may be suitable for administration via inhalation. Such formulation will likely be in liquid form and will be delivered in a spray bottle, in an inhaler, or in a nebulizer. Inhaled compositions are particularly suited for diseases and disorder, including infections, that affect the mammal's respiratory system and/or are transmitted via the mammal's respiratory system.

The dosage of any herein-disclosed composition or compositions can depend on several factors including the characteristics of the mammal to be administered. Examples of characteristics include species, strain, breed, sex, age, weight, size, health, and/or disease status. Moreover, the dosage may depend on whether the administration is the first time the subject received a composition of the present disclosure or if the subject has previously received a composition of the present disclosure. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a composition) information about a particular subject may affect dosage used. Furthermore, the exact individual dosages can be adjusted somewhat depending on a variety of factors, including the specific composition being administered, the time of administration, the route of administration, the nature of the formulation, and the rate of excretion. Some variations in the dosage can be expected.

Moreover, the dosage may depend on the specific ingredients administered.

In embodiments, the active agent (disulfiram) and/or the potentiating ingredient (cinnamaldehyde) are encapsulated in a microcapsules. Disulfiram may be encapsulated in one microcapsule and cinnamaldehyde may be encapsulated into another microcapsule. Disulfiram and cinnamaldehyde may be encapsulated into one microcapsule. Disulfiram may be encapsulated in one microcapsule and cinnamaldehyde may not be encapsulated. Disulfiram may not be encapsulated and cinnamaldehyde may be encapsulated in a microcapsule. The microcapsule may be a liposome, an albumin microsphere, a microemulsion, a nanoparticle (e.g., a lipid nanoparticle), and a nanocapsule. In embodiments, microcapsules, e.g., lipid nanoparticles and liposomes, include lipids selected from one or more of the following categories: cationic lipids; anionic lipids; neutral lipids; multi-valent charged lipids; and zwitterionic lipids. In some cases, a cationic lipid and/or cationic polymer may be used to facilitate a charge-charge interaction with disulfiram and/or the one or more additional ingredients. The microcapsule may comprise a PEGylated lipid. Examples of microcapsules and methods for manufacturing the same are described in the art. See, e.g., Prui et al., Crit Rev Ther Drug Carrier Syst., 2009; 26(6): 523-580; Wakasar, J Drug Target, 2018, 26(4):311-318, Langer, 1990, Science 249:1527-1533; Treat et al., in “Liposomes in the Therapy of Infectious Disease and Cancer”, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Pelaz et al. “Diverse applications of nanomedicine.” (2017): 2313-2381; the contents of each of which is incorporated herein by reference in its entirety.

Further, one or more additional ingredients (e.g., from Table 1) may be encapsulated and the disulfiram and/or cinnamaldehyde may be encapsulated, the one or more additional ingredients may be unencapsulated and disulfiram and/or cinnamaldehyde may be unencapsulated, and/or combinations thereof.

In embodiments, a composition may comprise one or more of capralactone, polylactide (PLA), polylactic-co-glycolic (PLGA), polyethylene glycol (PEG), polylactic-co-hydroxymethylglycolic acid (PLHMGA), carboxymethylcellulose, hydroxylmethylcellulose, gelatin-microcapsules, a poloxamer, or polymethylmethacrylate.

Disulfiram, as active agent, and cinnamaldehyde, as potentiating ingredient, may be administered to a subject in need thereof once per day, twice per day, or thrice per day. Disulfiram and cinnamaldehyde may be administered to a subject in need thereof once a week, twice a week, three times a week, four times a week, five times a week, or six times a week. Disulfiram and cinnamaldehyde may be administered to a subject in need thereof once a month, twice a month, three times a month, or four times a month.

When disulfiram and cinnamaldehyde are administered separately, i.e., in distinct compositions, the administration route of the first composition and the second composition may be the same or may be different. In one example, the first composition and the second composition are administrated orally. In one example, the first composition and the second composition are administrated by inhalation. In another example, the first composition is administrated orally and the second composition is by injection, inhalation, or topically. In yet another example, the first composition is administrated by inhalation and the second composition is by injection, orally, or topically.

Another aspect of the present disclosure is a composition comprising disulfiram as active agent and cinnamaldehyde as potentiating ingredient for use in any herein disclosed method. Yet another aspect of the present disclosure is a first composition comprising disulfiram and a second composition comprising cinnamaldehyde for use in any herein disclosed method.

Compositions of the present disclosure are formulated to be suitable for contacting a cell or an immune cell in vitro or ex vivo. In such embodiments, disulfiram and the one or more additional ingredients are formulated into a solution. The solute chosen depends on characteristics of the compound. For example, a water-soluble compound may be included in an aqueous solution, which comprises water or saline. A water-insoluble compound may be included in a non-aqueous solution, e.g., which comprises a lipid-based fluid or other hydrocarbon-based fluid. Disulfiram and the one or more additional ingredients may be formulated into a single solution. Alternately, disulfiram and the one or more additional ingredients may be formulated into distinct solutions.

Effectiveness of disulfiram and a specific additional ingredients may be validated in a pyroptosis inhibition assay. See, e.g., Example 3.

Illustrative Metal Additional Ingredients

In embodiments, the one or more additional ingredients is a metal. The metal may be selected from aluminum, calcium, copper, iron, magnesium, manganese, potassium, sodium, or zinc. Disulfiram has been shown to chelate certain metals and/or to be useful in the context of cancer treatments. See, e.g., Viola-Rhenals et al. “Recent Advances in Antabuse (Disulfiram): The Importance of its Metal-binding Ability to its Anticancer Activity”, Curr Med Chem. 2018 Feb. 12; 25(4): 506-524; WO2018081309A1; and WO2019094053A1. The contents of each of which is incorporated herein by reference in its entirety.

The metal may be in the form of any metal salt or metal ester described in the present FDA's list of food additives, e.g., as listed in Table 1.

In embodiments, the metal is aluminum, calcium, copper, iron, magnesium, manganese, potassium, sodium, or zinc.

In embodiments, aluminum is in the form of aluminum hydroxide, aluminum oxide, or aluminum potassium disulfate dodecahydrate.

In embodiments, calcium is in the form of anhydrous calcium sulfate, calcium carbonate, calcium citrate tetrahydrate, calcium gluconate, calcium glycerol phosphate, calcium hydrogen phosphate dihydrate, calcium hydroxide, calcium lactate, calcium orthophosphate, or calcium phosphate.

In embodiments, copper is in the form of copper (II) gluconate, copper sulfate, or copper (I) iodide.

In embodiments, iron is in the form of ferric ammonium citrate, iron, iron (II) fumarate, or iron (II) sulfate heptahydrate.

In embodiments, magnesium is in the form of magnesium hydroxide, magnesium oxide, or magnesium silicate.

In embodiments, manganese is in the form of manganese dichloride or manganese sulfate.

In embodiments, potassium is in the form of dipotassium carbonate, potassium bromide, or potassium chloride.

In embodiments, sodium is in the form of disodium 5′-inosinate, disodium succinate, sodium benzoate, sodium carbonate, sodium chloride, sodium citrate (dihydrate), sodium dodecyl sulfate, sodium formate, sodium gluconate, sodium thiosulfate (pentahydrate), or trisodium citrate.

In embodiments, zinc is in the form of zinc sulfate (heptahydrate).

In some embodiments, the dosage of disulfiram may be about 0.1-60 units and the amount of the one or more additional ingredients, which is a metal, may be about 1 unit, where disulfiram ranges from 5-500 mg. The amount of a metal (is an above-described form) may between 0.1 mg to 30 mg. In an embodiment, the amount of the metal is between 1.5 mg and 3 mg. In embodiments, the metal is copper or zinc and approximately 1.5 mg of the metal is administered.

Illustrative Methods

The present disclosure provides a method for increasing lifespan in a mammal, for preventing or treating disease including an aging-related disorder in a mammal, for reducing a symptom of aging in a mammal, and/or boosting an immune system in a mammal. The methods comprise administering to the mammal a therapeutically effective amount of disulfiram as active agent and cinnamaldehyde as potentiating ingredient. Disulfiram and cinnamaldehyde may be administered with one or more of the additional ingredients listed in Table 1.

In embodiments, route of administration is oral, by injection, inhalation, or topical. In embodiments, the injection is intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.

In embodiments, one composition comprising disulfiram is administered and a second composition comprising cinnamaldehyde is administered. In other embodiments, one composition comprising both disulfiram and cinnamaldehyde is administered.

In embodiments, the mammal is near or has reached maturity.

In embodiments, the mammal is nearing or has reached halfway to its expected lifespan for the mammal's species, size, sex, age, and/or health status. In embodiments, the mammal has reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal's species, size, sex, age, and/or health status.

In embodiments, increasing lifespan comprises an at least 5% increase in lifespan relative to the expected or median lifespan of a mammal of similar species, sex, age, and/or health status. In embodiments, increasing lifespan comprises an at least 10%, at least 15%, at least 20%, or at least 25% increase in lifespan.

In embodiments, the mammal is a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon. In embodiments, the mammal is a human.

Without wishing to be bound by theory, the active agent disulfiram and the potentiating ingredient cinnamaldehyde (with or without one or more additional ingredients, e.g., of Table 1) mitigates dysfunction of or rejuvenates a signaling pathway disrupted by aging where the dysfunction can ultimately lead to aging-related disorders. In embodiments, the aging-related disorder or symptom of aging selected from one or more of actinic keratosis, age-related macular degeneration (AMD), alopecia, Alzheimer's disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer (e.g., a skin cancer such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)), cardiomyopathy, cataracts, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, constipation, decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, dermal atrophy (thinning of the skin), diminished peripheral vision, dry eye, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza and pneumonia), lentigines (aging spots), memory loss, metabolic syndrome, muscle atrophy (e.g., Sarcopenia and myopenia), frailty, muscle repair or rejuvenation deficiency, muscular dystrophy, osteoarthritis, osteoporosis, periodontitis, photoaging, reduced metabolism (including increased risk for obesity), reduced reflexes and coordination including difficulty with balance, respiratory disease (including acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS)), rheumatoid arthritis, sarcopenic obesity, sexual dysfunction, shingles, type 2 diabetes, urologic changes (including incontinence), vaginal atrophy, whitening or graying of hair, prolonged/inefficient wound healing, wrinkling/sagging skin (including loss of skin elasticity), and xerosis cutis (skin dryness). In embodiments, the aging-related disorder or symptom of aging is actinic keratosis, dermal atrophy (thinning of the skin), lentigines (aging spots), photoaging, vaginal atrophy, prolonged/inefficient wound healing, wrinkles, and/or xerosis cutis (skin dryness) and the administration route is oral or topical. In embodiments, the mammal has at least one aging-related disorder or symptom of aging. A non-human mammal may have an aging-related disorder or symptom of aging that is homologous to the aging-related disorder or symptom of aging listed above.

In an embodiment, a composition comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde (with or without one or more additional ingredients, e.g., of Table 1) are administered to a mammal, e.g., a human, for preventing or treating a respiratory disease or disorder, e.g., acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS). Administration of the composition(s) is by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition(s) needing to be administered. Alternately, the composition(s) are administered orally, by inhalation, or topically. Combinations of administration routes may be used. Treatment is identified as an improvement in the administered mammal in one or more of the following symptoms severe shortness of breath, labored and unusually rapid breathing, low blood pressure, and confusion and extreme tiredness. The improvement may be relative to the pre-administration state for the mammal. The underlying cause for the ALI and/or ARDS may be sepsis (e.g., a serious and widespread infection of the bloodstream); inhalation of a harmful substance (e.g., smoke, chemical fumes, asbestos, dust, particulates, vomit, and water); viral or bacterial pneumonia (which may affect up to all five lobes of the lungs) and other respiratory disorders including those caused by a coronavirus (e.g., SARS, MERS, and COVID-19), influenzas (influenza A, influenza B, or parainfluenza), pneumococcal infection, adenovirus, respiratory syncytial virus (RSV), enterovirus and/or other respiratory viral infections; and a head, chest or other major injury; or another cause (e.g., pancreatitis which is inflammation of the pancreas, a massive blood transfusion, and severe burns). In some embodiments, ALI differs from ARDS in that ALI exists during early stage of a respiratory disease and ARDS exists during a later state of the respiratory disease. In some, the composition or compositions prevent or treat idiopathic pulmonary fibrosis and/or chronic obstructive pulmonary disease.

In an embodiment, a composition comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde (with or without one or more additional ingredients, e.g., of Table 1) are administered to a mammal, e.g., a human, for treating dry eye. The composition(s) may be administered topically (e.g., via eye drops or an eye ointment), with a dose depending on the quantity of composition(s) needing to be administered.

In an embodiment, a composition comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde (with or without one or more additional ingredients, e.g., of Table 1) are administered to a mammal, e.g., a human, for treating alopecia. The composition(s) may be administered topically (e.g., gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, or aerosol or via an impregnated solid support (e.g., a patch)), with a dose depending on the quantity of composition(s) needing to be administered. The composition may be administered orally, by injection, or by inhalation.

In an embodiment, a composition comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde (with or without one or more additional ingredients, e.g., of Table 1) are administered to a mammal, e.g., a human, for treating a skin disorder, e.g., wrinkles, which may be a result of photoaging or related to actinic keratosis. Other skin disorders include dermal atrophy (thinning of the skin), lentigines (aging spots), vaginal atrophy, prolonged/inefficient wound healing, and/or xerosis cutis (skin dryness). The composition(s) may be formulated as a gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, or aerosol or administered via an impregnated solid support (e.g., a patch)). The composition(s) may be administered orally or topically, with a dose depending on the quantity of composition(s) needing to be administered. Alternately, the composition(s) may be administered by injection or by inhalation. Combinations of administration routes may be used.

In an embodiment, a composition comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde (with or without one or more additional ingredients, e.g., of Table 1) are administered to a mammal, e.g., a human, for treating a skin cancer, e.g., (e.g., basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)). The compositions may be administered topically, with a dose depending on the quantity of composition needing to be administered. The compositions may be formulated as a gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, or aerosol or administered via an impregnated solid support (e.g., a patch)). Alternately, the composition may be administered orally, by injection, or by inhalation. Combinations of administration routes may be used.

In embodiments, a therapeutically effective amount of disulfiram as active agent and cinnamaldehyde as potentiating ingredient (with or without one or more additional ingredients, e.g., of Table 1) treats or prevents a disease or a symptom thereof, as examples, the disease may be asthma, deafness, or a viral infections and a symptom thereof may be sepsis.

In embodiments, a therapeutically effective amount of the active agent disulfiram and the potentiating ingredient cinnamaldehyde (with or without one or more additional ingredients, e.g., of Table 1) boosts the immune system in the mammal.

As shown in Example 2, cells from older donors treated with disulfiram exhibited phenotypes of younger cells in response to viral infection. Further, disulfiram reduced inflammasome-mediated pyroptotic cell death. Importantly, the combination of disulfiram and cinnamaldehyde showed a synergistic effect on reduction of inflammasome activation, as shown in Example 3.

In embodiments, boosting the immune system increases an effective immune response against an infectious agent. In embodiments, the infectious agent is a virus, a bacterium, a fungus, a protozoan, a helminth, a prion, or a parasite. In embodiments, the bacterium is Bordatella pertussis or Streptococcocus pneumoniae or the virus is a Chickenpox virus, Coronavirus, Hepatitis A virus, Hepatitis B virus, Human papillomavirus, Human immunodeficiency virus (HIV), influenza, Japanese encephalitis virus, Measles, mumps, or rubella virus, Poliovirus, Rabies virus, Respiratory syncytial virus (RSV), Rotavirus, Shingles virus, Smallpox, Varicella virus, or Yellow fever virus. In embodiments, the Coronavirus is Sars-CoV-2. In embodiments, when the infectious agent affects the mammal's respiratory system or is transmitted via the mammal's respiratory system and the route of administration is by inhalation.

In embodiments, the route of administration is oral or by inhalation.

In embodiments, the mammal has a healthy immune system. In embodiments, the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.

The present disclosure provides an in vivo method for increasing lifespan of a cell and/or boosting activity of an immune cell comprising contacting the cell or the immune cell with disulfiram as active agent and cinnamaldehyde as potentiating ingredient. In some embodiments, the immune cell is contacted with disulfiram and cinnamaldehyde and one or more of the additional ingredients listed in Table 1. In such in vivo methods, disulfiram and cinnamaldehyde (with or without one or more additional ingredients) are administered to a subject, e.g., parenterally or enterally, and disulfiram and cinnamaldehyde (with or without the one more additional ingredients) contacts the cell or immune cell within the subject, e.g., by being carried through the subject's blood stream or the subject's lymphatic system or within extracellular spaces.

The present disclosure provides an in vitro or ex vivo method for increasing lifespan of a cell and/or boosting activity of an immune cell, the method comprises contacting the cell or the immune cell with a disulfiram as active agent and cinnamaldehyde as potentiating ingredient (with or without one or more of the additional ingredients listed in Table 1). Here, the cell or the immune cell is in a culturing vessel, e.g., a petri dish, tissue culture plate, or culture flask, and disulfiram and cinnamaldehyde (at least) are added to a medium (e.g., growth medium or buffer solution) surrounding the cell or immune cell.

In some methods, the one or more additional ingredients is a metal (e.g., copper and zinc).

Boosting the Immune System

Another aspect of the present disclosure is a method for boosting the immune system in a mammal.

The method for boosting an immune system in a mammal comprises administering to the mammal a therapeutically effective amount of disulfiram as active agent and cinnamaldehyde as potentiating ingredient, with or without one or more of the additional ingredients listed in Table 1.

In embodiments, boosting the immune system increases an effective immune response against an infectious agent. In embodiments, the infectious agent is a virus, a bacterium, a fungus, a protozoan, a helminth, a prion, or a parasite. In embodiments, the bacterium is Bordatella pertussis or Streptococcocus pneumoniae. In embodiments, the virus is selected from Alphavirus, BK virus, Bunyaviridae, Chickenpox virus, Colorado tick fever virus (CTFV), Coronaviruse, Crimean-Congo hemorrhagic fever virus, Cytomegalovirus, Dengue viruses (DEN-1, DEN-2, DEN-3 and DEN-4), Ebolavirus (EBOV), Enteroviruses, mainly Coxsackie A virus and enterovirus 71 (EV71), Epstein-Barr virus (EBV), Flaviviruses, Guanarito virus, Heartland virus, Hendra virus, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis D Virus, Hepatitis E virus, Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), Human bocavirus (HBoV), Human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7), Human immunodeficiency virus (HIV), Human metapneumovirus (hMPV), Human papillomaviruses (HPV), Human parainfluenza viruses (HPIV), Influenza, Japanese encephalitis virus, JC virus, Junin virus, Lassa virus, Lymphocytic choriomeningitis virus (LCMV), Machupo virus, Marburg virus, Measles virus, Middle East respiratory syndrome coronavirus, Molluscum contagiosum virus (MCV), Monkeypox virus, Mumps virus, Nipah virus, Norovirus, Orthomyxoviridae species, Parvovirus B19, Poliovirus, Rabies virus, Respiratory syncytial virus (RSV), Rhinovirus, Rift Valley fever virus, Rotavirus, Rubella virus, Sabia virus, SARS coronavirus, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Shingles virus, Sin Nombre virus, Smallpox, Varicella zoster virus (VZV), Variola major or Variola minor, Venezuelan equine encephalitis virus, West Nile virus, Yellow fever virus, and Zika virus. In embodiments, the Coronavirus is Sars-CoV-2.

In embodiments, when the infectious agent affects the mammal's respiratory system or is transmitted via the mammal's respiratory system and the route of administration is by inhalation.

In embodiments, the route of administration is oral or by inhalation.

In some cases, the mammal has a healthy immune system. In other cases, the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.

In embodiments, the term dysfunctional immune system may be an overactive immune system, e.g., resulting in a cytokine storm; such overactive immune systems are observed in certain viral infections, e.g., in some severe coronavirus patients. In various embodiments, “boosting the immune system”, relates to “boosting” a proper (e.g., non-pathological) immune response. That is, minimizing an overactive immune response.

In embodiments, the mammal is nearing or has reached halfway to its expected lifespan for the mammal's species, size, sex, age, and/or health status. In embodiments, the aged mammal has reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal's species, size, sex, age, and/or health status.

Of course, any mammal may benefit from a boost in the immune system. Thus, the compositions and methods for boosting the immune system can be used with aged and with non-aged mammals.

In embodiments, the route of administration is oral, by injection, inhalation, or topical. The administration route may comprise intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.

In embodiments, one composition comprising the active agent that is disulfiram is administered and a second composition comprising the potentiating ingredient that is cinnamaldehyde. In other embodiments, one composition comprising both disulfiram and cinnamaldehyde is administered.

In some embodiments, one or more additional ingredients, e.g., of Table 1, is included in the composition with disulfiram and cinnamaldehyde, in the composition with disulfiram, in the composition with cinnamaldehyde, or in a composition without disulfiram or cinnamaldehyde.

In methods for boosting the immune system in a mammal, the one or more additional ingredients may be a metal (e.g., copper and zinc).

Improving a Vaccine Response

The present disclosure also provides a method for improving effectiveness of a vaccine in a mammal in need thereof. The method comprises administering a therapeutically effective amount of disulfiram as active agent and cinnamaldehyde as potentiating ingredient, with or without one or more of the additional ingredients listed in Table 1. Here, the mammal may contemporaneously and/or subsequently be administered a vaccine.

In embodiments, disulfiram and cinnamaldehyde (with or without one or more additional ingredients, e.g., of Table 1) and the vaccine are administered contemporaneously. In embodiments, the vaccine is administered subsequent to administering disulfiram and cinnamaldehyde, with or without one or more additional ingredients.

In embodiments, a therapeutically effective amount of disulfiram and cinnamaldehyde (with or without the one or more of the additional ingredients) boosts the immune system in the mammal.

In embodiments, boosting the immune system increases an immune response against a component contained in the vaccine. In embodiments, the increased immune response promotes future immunity against the component contained in the vaccine.

It has been reported in the art that aged mammals respond less strongly to vaccines than mammal who are less aged. Accordingly, methods for improving effectiveness of a vaccine in an aged mammal are needed.

In embodiments, an aged mammal is nearing or has reached halfway to its expected lifespan for the mammal's species, size, sex, age, and/or health status. In embodiments, the aged mammal has reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal's species, size, sex, age, and/or health status.

Influenza is problematic in older adults with increased risk for serious complications and hospitalization. In addition, approximately 90% of flu-related deaths occur in this population, with influenza and pneumonia being the eighth leading cause of death among persons over 65 years of age in the United States. Even when death is avoided, older adults have an increased risk for secondary complications and morbidities from flu infection. Depending on how successful the WHO predicts the influenza strains causing seasonal epidemics, the produced vaccines show efficacy rates between 60% and 90%. However, vaccine effectiveness in adults aged 65 and older is usually significantly lower, ranging from an average of 28% protection against fatal and nonfatal complications (with large dispersion), 39% protection against typical influenza-like illness, and 49% protection against disease with confirmed virus infection. Influenza vaccine effectiveness is a significant problem in elderly as compared to young individuals and is associated with high rates of complicated illness including pneumonia, heart attacks, and strokes in the >65-year-old population.

Furthermore, the outbreak of the novel coronavirus (SARS-CoV-2) has had devastating effects on the aged and those with pre-existing health conditions. A mammal would particularly benefit from a composition of the present disclosure and methods of administering the same to improve effectiveness of a SARS-CoV-2 vaccine.

Of course, mammals who are not aged may benefit from improved effectiveness of a vaccine. Thus, the compositions and methods for improving effectiveness of a vaccine can be used with non-aged mammals.

In some cases, the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system. In other cases, the mammal has a healthy immune system.

In embodiments, the term dysfunctional immune system may be an overactive immune system, e.g., resulting in a cytokine storm; such overactive immune systems are observed in certain viral infections, e.g., in some severe coronavirus patients. In various embodiments, “improving a vaccine response”, relates to “improving” a proper (e.g., non-pathological) immune response to a vaccine and, later, when a subject is contacted with an infectious agent. That is, minimizing an overactive immune response and promoting a proper immune response.

In embodiments, the increased immune response promotes future immunity against the component contained in the vaccine. In embodiments, the component contained in the vaccine is an antigen obtained from, related to, homologous to, or expressed by an infectious agent.

In embodiments, the vaccine is a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human Immunovirus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (part of the DTaP combined vaccine) vaccine, or Yellow fever vaccine. In embodiments, the vaccine is a coronavirus vaccine, e.g., directed against Sars-CoV-2.

In embodiments, disulfiram and cinnamaldehyde (with or without one or more of the additional ingredients) is administered orally, by injection, by inhalation, or topically. In embodiments, the vaccine is administered orally, by injection, by inhalation, or topically. In embodiments, the injection is intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.

In embodiments, one composition comprising disulfiram as active agent is administered and a second composition comprising cinnamaldehyde as potentiating ingredient is administered. Here, a third composition comprising on or more additional ingredients, e.g., of Table 1, is administrated. In other embodiments, one composition comprising both disulfiram and cinnamaldehyde (with or without the one or more additional ingredients) is administered.

In methods for improving effectiveness of a vaccine, the one or more additional ingredients may be a metal (e.g., copper and zinc).

2. Reducing the Predicted Age of Cell

An aspect of the present disclosure is a method for reducing a predicted biological age of a cell. The method comprises contacting the cell with a therapeutically effective amount of the active agent disulfiram and the potentiating ingredient cinnamaldehyde, with or without one or more additional ingredients listed in Table 1.

As shown in Example 2, cells from older donors treated with disulfiram exhibited phenotypes similar to younger donors. For instance, disulfiram significantly reduced several proinflammatory cytokines and significantly reduced the percentage of mitochondria with reticular shape. In addition, T cells from older donors treated with disulfiram exhibited a younger phenotype as compared to untreated controls.

In embodiments, the cell is in vitro, ex vivo, or in vivo.

In methods for reducing a predicted biological age of a cell, the one or more additional ingredients may be a metal (e.g., copper and zinc).

Assays and formulations used in methods for reducing a predicted biological age of a cell may be related to those described in US20190228840, the entire contents of which is incorporated by reference its entirety.

Aging-Related Disorders

The herein-disclosed compositions and methods treat, prevent, reduce the severity of, and/or delay the onset of various aging-related disorders, e.g., chronic diseases and disabilities/conditions of aging. Illustrative aging-related disorders include actinic keratosis, age-related macular degeneration (AIMD), alopecia, Alzheimer's disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer (e.g., a skin cancer including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)), cardiomyopathy, cataracts, chronic obstructive pulmonary disease (COPD), constipation, decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, dermal atrophy (thinning of the skin), diminished peripheral vision, dry eye, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza and pneumonia), lentigines (aging spots), memory loss, metabolic syndrome, muscle atrophy (e.g., Sarcopenia and myopenia), frailty, muscle repair or rejuvenation deficiency, muscular dystrophy, osteoarthritis, osteoporosis, periodontitis, photoaging, reduced metabolism (including increased risk for obesity), reduced reflexes and coordination including difficulty with balance, respiratory disease (including acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS)), rheumatoid arthritis, sarcopenic obesity, sexual dysfunction, shingles, type 2 diabetes, urologic changes (including incontinence), vaginal atrophy, whitening or graying of hair, wrinkling/sagging skin (including loss of skin elasticity), and xerosis cutis (skin dryness). Aged non-human subjects experience similar, homologous, and/or equivalent aging-related disorders.

Without wishing to be bound by theory, disulfiram and the one or more additional ingredients mitigates dysfunction of or rejuvenates a signaling pathway disrupted by aging where the dysfunction can ultimately lead to aging-related disorders.

3. Inhibiting Pyroptosis

In any of the herein-disclosed aspects and embodiments, use of disulfiram as active agent and cinnamaldehyde as potentiating ingredient, with or without one or more additional ingredients, e.g., of Table 1, inhibits pyroptosis of a cell.

Pyroptosis is a highly inflammatory form of programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial innate immune response. Pyroptosis results in a distinct morphology by a unique mechanism compared to those of other forms of cell death. For example, unlike apoptosis-type programmed cell death, in a cell that undergoes pyroptosis, gasdermin D pores are formed on the plasma membrane, resulting in water influx and cell lysis, and in some cases, release of IL-1β, IL-18 and HMGB1.

The potentiating ingredient cinnamaldehyde enhances disulfiram's ability to inhibit pyroptosis, as shown in Example 3.

Subjects

In embodiments, the subject is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon. In embodiments, the mammal is a non-rodent. In embodiments, the mammal is a dog. In embodiments, the subject is a non-human animal, and therefore the invention pertains to veterinary use. In a specific embodiment, the non-human animal is a household pet, e.g., a dog. In another specific embodiment, the non-human animal is a livestock animal. In embodiments, the mammal is a human.

In embodiments, the mammal has reached maturity. As used herein, the term mature or maturity, and the like, refers to a mammal that is capable of sexual reproduction and/or a mammal that has achieved its adult height and/or length.

In embodiments, the mammal is nearing or has reached halfway to its expected lifespan for the mammal's species, size, sex, age, and/or health status. The mammal may have reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal's species, size, sex, age, and/or health status.

In embodiments, the human is an adult human. In embodiments, the human has an age in a range of from about 10 to about 15 years old, from about 15 to about 20 years old, from about 20 to about 25 years old, from about 25 to about 30 years old, from about 30 to about 35 years old, from about 35 to about 40 years old, from about 40 to about 45 years old, from about 45 to about 50 years old, from about 50 to about 55 years old, from about 55 to about 60 years old, from about 60 to about 65 years old, from about 65 to about 70 years old, from about 70 to about 75 years old, from about 75 to about 80 years old, from about 80 to about 85 years old, from about 85 to about 90 years old, from about 90 to about 95 years old or from about 95 to about 100 years old, or older.

In some cases, the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system. In other cases, the mammal has a healthy immune system.

FURTHER EMBODIMENTS Embodiment 1

A method for increasing lifespan in a mammal, for preventing or treating disease including an aging-related disorder in a mammal, for reducing a symptom of aging in a mammal, and/or boosting an immune system in a mammal comprising: administering to the mammal one or more compositions that each or together comprise an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde.

Embodiment 2

An in vivo, in vitro, or ex vivo method for increasing lifespan of a cell and/or boosting activity of an immune cell comprising contacting the cell or the immune cell with one or more compositions that each or together comprise an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde.

Embodiment 3

The method of embodiment 1 or embodiment 2, wherein one composition is administered that consists essentially of disulfiram and cinnamaldehyde.

Embodiment 4

The method of embodiment 1 or embodiment 2, wherein more than one composition is administered with a first composition consisting essentially of disulfiram and with a second composition consisting essentially of cinnamaldehyde.

Embodiment 5

The method of any one of embodiments 1 to 4, wherein the one or more compositions independently further comprises one or more additional ingredients from Table 1.

Embodiment 6

The method of any one of embodiments 1 to 5, wherein the administering is oral, by injection, inhalation, or topical.

Embodiment 7

The method of any one of embodiments 1 to 6, wherein the mammal is near or has reached maturity.

Embodiment 8

The method of any one of embodiments 1 to 6, wherein the mammal is nearing or has reached halfway to its expected lifespan for the mammal's species, size, sex, age, and/or health status.

Embodiment 9

The method of any one of embodiments 1 to 6, wherein the mammal has reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal's species, size, sex, age, and/or health status.

Embodiment 10

The method of any one of embodiments 1 to 9, wherein the mammal is a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon.

Embodiment 11

The method of embodiment 10, wherein the mammal is a human.

Embodiment 12

The method of any one of embodiments 1 to 11, wherein increasing lifespan comprises an at least 5% increase in lifespan relative to the expected or median lifespan of a mammal of similar species, sex, age, and/or health status.

Embodiment 13

The method of embodiment 12, wherein increasing lifespan comprises an at least 10%, at least 15%, at least 20%, or at least 25% increase in lifespan.

Embodiment 14

The method of any one of embodiments 1 to 13, wherein the aging-related disorder or symptom of aging selected from one or more of actinic keratosis, age-related macular degeneration (AIMD), alopecia, Alzheimer's disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer (e.g., a skin cancer including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)), cardiomyopathy, cataracts, chronic obstructive pulmonary disease (COPD), constipation, decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, dermal atrophy (thinning of the skin), diminished peripheral vision, dry eye, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza and pneumonia), lentigines (aging spots), memory loss, metabolic syndrome, muscle atrophy (e.g., Sarcopenia and myopenia), frailty, muscle repair or rejuvenation deficiency, muscular dystrophy, osteoarthritis, osteoporosis, periodontitis, photoaging, reduced metabolism (including increased risk for obesity), reduced reflexes and coordination including difficulty with balance, respiratory disease (including acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS)), rheumatoid arthritis, sarcopenic obesity, sexual dysfunction, shingles, type 2 diabetes, urologic changes (including incontinence), vaginal atrophy, whitening or graying of hair, prolonged/inefficient wound healing, wrinkling/sagging skin (including loss of skin elasticity), and xerosis cutis (skin dryness); or the disease includes asthma, deafness, or a viral infections and/or a symptom of the disease comprises sepsis.

Embodiment 15

The method of embodiment 14, wherein the aging-related disorder or symptom of aging is actinic keratosis, dermal atrophy (thinning of the skin), lentigines (aging spots), photoaging, vaginal atrophy, prolonged/inefficient wound healing, wrinkles, and/or xerosis cutis (skin dryness) and wherein the administering is oral or topical.

Embodiment 16

The method of embodiment 14 or embodiment 15, wherein the mammal has at least one aging-related disorder or symptom of aging.

Embodiment 17

The method of any one of embodiments 1 to 16, wherein the disulfiram and the cinnamaldehyde boosts the immune system in the mammal.

Embodiment 18

The method of embodiment 17, wherein boosting the immune system increases an effective immune response against an infectious agent.

Embodiment 19

The method of embodiment 18, wherein the infectious agent is a virus, a bacterium, a fungus, a protozoan, a helminth, a prion, or a parasite.

Embodiment 20

The method of embodiment 19, wherein the bacterium is Bordatella pertussis or Streptococcocus pneumoniae or the virus is a Chickenpox virus, Coronavirus, Hepatitis A virus, Hepatitis B virus, Human papillomavirus, Human immunodeficiency virus (HIV), influenza (e.g., Influenza A, Influenza B, and parainfluenza), Japanese encephalitis virus, Measles, mumps, or rubella virus, Poliovirus, Rabies virus, Respiratory syncytial virus (RSV), Rotavirus, Shingles virus, Smallpox, Varicella virus, or Yellow fever virus.

Embodiment 21

The method of embodiment 20, wherein the Coronavirus is Sars-CoV-2.

Embodiment 22

The method of any one of embodiments 18 to 21, wherein the infectious agent affects the mammal's respiratory system or is transmitted via the mammal's respiratory system and wherein the administering is orally or by inhalation.

Embodiment 23

The method of any one of embodiments 1 to 22, wherein the mammal has a healthy immune system.

Embodiment 24

The method of any one of embodiments 1 to 22, wherein the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.

Embodiment 25

A method for improving effectiveness of a vaccine in a mammal in need thereof, the method comprises administering a therapeutically effective amount of one or more compositions that each or together comprise an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde, wherein the mammal contemporaneously and/or subsequently will be administered a vaccine.

Embodiment 26

The method of embodiment 25, wherein one composition is administered that consists essentially of disulfiram and cinnamaldehyde.

Embodiment 27

The method of embodiment 25, wherein more than one composition is administered with a first composition consisting essentially of the disulfiram and with a second composition consisting essentially of cinnamaldehyde.

Embodiment 28

The method of any one of embodiments 25 to 27, wherein the one or more compositions independently further comprises one or more additional ingredients from Table 1.

Embodiment 29

The method of any one of embodiments 25 to 28, wherein the one or more compositions and the vaccine are administered contemporaneously.

Embodiment 30

The method of any one of embodiments 25 to 29, wherein the vaccine is administered subsequent to administering the one or more composition.

Embodiment 31

The method of any one of embodiments 25 to 30, wherein the therapeutically effective amount of the one or more compositions boosts the immune system in the mammal.

Embodiment 32

The method of embodiment 31, wherein boosting the immune system increases an immune response against a component contained in the vaccine.

Embodiment 33

The method of embodiment 32, wherein the increased immune response promotes future immunity against the component contained in the vaccine.

Embodiment 34

The method of any one of embodiments 25 to 33, wherein the component contained in the vaccine is an antigen obtained from, related to, homologous to, or expressed by an infectious agent.

Embodiment 35

The method of any one of embodiments 25 to 34, wherein the vaccine is a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human Immunovirus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (part of the DTaP combined vaccine) vaccine, or Yellow fever vaccine.

Embodiment 36

The method of embodiment 34, wherein the vaccine is a coronavirus vaccine, e.g., Sars-CoV-2.

Embodiment 37

The method of any one of embodiments 25 to 36, wherein the mammal has a healthy immune system.

Embodiment 38

The method of any one of embodiments 25 to 36, wherein the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.

Embodiment 39

The method of any one of embodiments 25 to 38, wherein the administering of the one or more compositions is oral, by injection, inhalation, or topical.

Embodiment 40

The method of any one of embodiments 25 to 39, wherein the administering of the vaccine is oral, by injection, inhalation, or topical.

Embodiment 41

The method of any one of embodiments 1 to 40, wherein the disulfiram is administered in a dose from about 5 to about 500 mg.

Embodiment 42

The method of any one of embodiments 1 to 41, wherein the cinnamaldehyde is administered in a dose from about 0.01% to about 45% of the weight of the disulfiram.

Embodiment 43

The method of any one of embodiments 1, 2, 4-25, or 27-42, wherein the one or more compositions independently further comprises a metal.

Embodiment 44

The method of embodiment 43, wherein the metal aluminum, calcium, copper, iron, magnesium, manganese, potassium, sodium, or zinc.

Embodiment 45

The method of embodiment 44, wherein the metal is aluminum hydroxide, aluminum oxide, aluminum potassium disulfate dodecahydrate, anhydrous calcium sulfate, calcium carbonate, calcium citrate tetrahydrate, calcium gluconate, calcium glycerol phosphate, calcium hydrogen phosphate dihydrate, calcium hydroxide, calcium lactate, calcium orthophosphate, calcium phosphate, copper (II) gluconate, copper sulfate, copper (I) iodide, ferric ammonium citrate, iron, iron (II) fumarate, iron (II) sulfate heptahydrate, magnesium hydroxide, magnesium oxide, magnesium silicate, manganese dichloride, manganese sulfate, dipotassium carbonate, potassium bromide, potassium chloride, disodium 5′-inosinate, disodium succinate, sodium benzoate, sodium carbonate, sodium chloride, sodium citrate (dihydrate), sodium dodecyl sulfate, sodium formate, sodium gluconate, sodium thiosulfate (pentahydrate), trisodium citrate, or zinc sulfate (heptahydrate).

Embodiment 46

The method of embodiment 45 wherein the metal is copper (II) gluconate, copper sulfate, copper (I) iodide, or zinc sulfate (heptahydrate).

Embodiment 47

The method of any one of embodiments 42 to 46, wherein the amount of the metal is between about 0.1 mg to about 30 mg.

Embodiment 48

The method of embodiment 47, wherein the amount of the metal is between about 1.5 mg and 3 mg.

Embodiment 49

The method of embodiment 48, wherein the metal is copper or zinc and approximately 1.5 mg of the metal is administered per dose.

Embodiment 50

A method for reducing a predicted biological age of a cell comprising contacting the cell with a therapeutically effective amount of one or more compositions that each or together comprise an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde.

Embodiment 51

The method of embodiment 50, wherein one composition is administered that consists essentially of disulfiram and cinnamaldehyde.

Embodiment 52

The method of embodiment 50, wherein more than one composition is administered with a first composition consisting essentially of disulfiram and with a second composition consisting essentially of cinnamaldehyde.

Embodiment 53

The method of any one of embodiments 50 to 52, wherein the one or more compositions independently further comprises one or more additional ingredients from Table 1.

Embodiment 54

The method of any one of embodiments 50 to 53, wherein the cell is in vitro, ex vivo, or in vivo.

Embodiment 55

The method of any one of embodiments 1 to 54, wherein the disulfiram inhibits pyroptosis of a cell.

Embodiment 56

The method of embodiment 55, wherein the cinnamaldehyde potentiates disulfiram's inhibition of pyroptosis of a cell.

Embodiment 57

The method of any one of embodiments 1 to 56, wherein the one or more compositions inhibits pyroptosis of a cell.

Embodiment 58

One or more compositions that each or together comprise an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde for use in the method of any one of embodiments 1 to 56.

Embodiment 59

The one or more compositions of embodiment 58, wherein the disulfiram is in an amount from about 5 mg to about 500 mg.

Embodiment 60

The one or more compositions of embodiment 58 or embodiment 59, wherein the cinnamaldehyde is in an amount from about 0.01% to about 45% of the weight of the disulfiram.

Embodiment 61

A composition comprising an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde.

Embodiment 62

The composition of embodiment 61, wherein the composition consists essentially of disulfiram and cinnamaldehyde.

Embodiment 63

The composition of embodiment 61 or embodiment 62, further comprising one or more additional ingredients from Table 1.

Embodiment 64

The composition of any one of embodiments 61 to 63, wherein the disulfiram is in an amount from about 5 mg to about 500 mg.

Embodiment 65

The composition of any one of embodiments 61 to 64, wherein the cinnamaldehyde is in an amount from about 0.01% to about 45% by weight of the disulfiram.

REFERENCES

The following references are incorporated into this disclosure: Hu et al., “FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation.” Nature Immunology (2020): 1-10; Liu et al., “Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores.” Nature. 2016; 535(7610):153-158; McCarthy A. “Disulfiram inhibits inflammatory gatekeeper protein: Could it be helpful in COVID-19”. Boston Children's Press Release. 10 May 2020; WO2020006229A1; WO2016/086008; Lin, et al. “Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes”. Antiviral Res. 2018; 150:155-163; Loo and Clarke “Blockage of drug resistance in vitro by disulfiram, a drug used to treat alcoholism.” J Natl Cancer Inst. 2000; 92(11):898-902; Sauna et al., “The molecular basis of the action of disulfiram as a modulator of the multidrug resistance-linked ATP binding cassette transporters MDR1 (ABCB1) and MRP1 (ABCC1).” Mol Pharmacol. 2004; 65(3):675-684; and Cheung et al., “Cinnamic compound metabolism in human skin and the role metabolism may play in determining relative sensitisation potency”. J Dermatol Sci. 2003 February; 31(1):9-19. Each of the above-mentioned documents is incorporated by reference in its entirety

DEFINITIONS

The terminology used herein is for the purpose of describing particular cases only and is not intended to be limiting.

The term “disulfiram” includes the compound disulfiram itself as well as its metabolites and/or derivatives. The term “additional ingredient(s)” includes the additional ingredient(s) as well as its/their metabolites, derivatives, and/or precursors.

As used herein, unless otherwise indicated, the terms “a”, “an” and “the” are intended to include the plural forms as well as the single forms, unless the context clearly indicates otherwise.

The terms “comprise”, “comprising”, “contain,” “containing,” “including”, “includes”, “having”, “has”, “with”, or variants thereof as used in either the present disclosure and/or in the claims, are intended to be inclusive in a manner similar to the term “comprising.”

By preventing is meant, at least, avoiding the occurrence of a disease and/or reducing the likelihood of acquiring the disease. By treating is meant, at least, ameliorating or avoiding the effects of a disease, including reducing a sign or symptom of the disease.

The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean 10% greater than or less than the stated value. In another example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the given value. Where particular values are described in the application and claims, unless otherwise stated the term “about” should be assumed to mean an acceptable error range for the particular value.

By “one or more” is meant at least one, e.g., one, two, three, four, five, six, seven, eight, nine, ten or more.

The “boosting the immune system”, in various embodiments, relates to “boosting” a proper (e.g., non-pathological) immune response. In some cases, this will minimize an overactive immune response. In embodiments, the term dysfunctional immune system may be an overactive immune system, e.g., resulting in a cytokine storm; such overactive immune systems are observed in certain viral infections, e.g., in some severe coronavirus patients. In other cases, this will improve, activate, and/or enhance a proper immune response, e.g., when exposed to a vaccine comprising an antigen obtained from, related to, homologous to, or expressed by an infectious agent, when exposed to an infectious agent, and/or when exposed to an atypical cell in need of being attacked by an immune cell.

Any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.

EXAMPLES

The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the present invention in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes therein and other uses which are encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art.

Example 1: Identification of Combinations of Disulfiram and Potentiating Ingredients Useful in Methods of the Present Disclosure

In this example, disulfiram and potentiating ingredients capable of increasing lifespan in a mammal, of preventing or treating a disease including an aging-related disorder in a mammal, of reducing a symptom of aging in a mammal, and/or of boosting an immune system were identified.

Sets of cultured cells—fibroblasts, peripheral blood mononuclear cells (PBMCs including lymphocytes and monocytes, and/or myoblasts—having either characteristics of young cells or characteristics of old cells were contacted with a combination of disulfiram and one or more potentiating ingredients from Table 1. The ability of disulfiram and one or more potentiating ingredients to reverse aging in the cells, e.g., reducing the characteristics of old cells and promoting characteristics of a young cells was assayed (also known as reducing the predicted age of the cells). Disulfiram and one or more potentiating ingredients were used at various concentrations ranging from 0.000005 to 80 μM. In some cases, the concentration of disulfiram was as high as 80 μM and the concentration of the potentiating ingredient was as high as 25 μM. Combinations of disulfiram and one or more potentiating ingredients showing the ability to reverse aging were further validated.

Assays and formulations used in this example are related to those described in US20190228840, the entire contents of which is incorporated by reference its entirety.

In this experiment, cinnamaldehyde was identified as a potentiating ingredient.

Example 2: Phenotypic Effect of Disulfiram on Immune Cells

In this example, disulfiram was shown to modify quantifiable parameters in virally infected cells from older donors that reflects those observed in cells from younger donor.

Whole blood from younger and older donors was collected into EDTA tubes and then diluted with an equal volume of phosphate-buffered saline (PBS)+2% fetal bovine serum (FBS) and layered over Ficoll using SepMate™-50 tubes (STEMCELL Technologies Inc., Vancouver, Canada). Cells were centrifuged at 1200 g for 10 min at room temperature, and the top plasma layer was removed. Peripheral blood mononuclear cells (PBMCs) were collected, washed with PBS+2% FBS, and counted using acridine orange/propidium iodide using a Cellometer® Vision CBA (Nexcelom Bioscience, Lawrence, Mass., USA). PBMCs were cryopreserved in CryoStor® CS10 (BioLife Solutions, Bothell, Wash., USA), frozen using CoolCell® FTS30 freezing containers (BioCision, San Rafael, Calif., USA), and stored in the liquid nitrogen vapor phase until use.

Specific cell types were isolated from the PBMC fraction using the following kits (STEMCELL Technologies Inc.) per manufacturer's recommendations: EasySep™ Human T Cell Enrichment Kit (T cells); EasySep™ Human B Cell Enrichment Kit (B cells); EasySep™ Human NK Cell Enrichment Kit (NK cells); and EasySep™ Human Monocyte Enrichment Kit (monocytes). T cells (CD3+), B cells (CD19+), natural killer (NK) cells (CD59+), and monocytes (CD14+) were isolated based on their customarily defined gene expression markers. Isolated cells were counted using acridine orange/propidium iodide on a Cellometer Vision CBA and then cryopreserved as described above until use.

After cells undertook a 30-min adhesion onto a 384-well assay plate, 10 μL of 5× trigger medium (including vesicular stomatitis virus encoding a red fluorescent protein (rVSV-ΔG-mCherry), DMSO, test compound, and FBS) was added to the assay plate using a 384-well pipetting head to achieve a final concentration of rVSV-ΔG-mCherry at 10×MOI, 0.1% DMSO, 10% FBS, and 0.33 μM or 5.3 μM compound concentration. The assay plate was centrifuged for 1 min at 138×g and incubated for 24 h at 37° C. with 5% humidity.

rVSV-ΔG-mCherry infected monocytes and macrophages, which subsequently created a highly inflamed environment for the lymphocytes and other cells. rVSV-ΔG-mCherry was used because of its ability to model the innate immune activation pathways of prevalent respiratory RNA viruses and because it was safe to use in a high-throughput laboratory with biosafety level one.

Virally infected cells were contacted with different concentrations of disulfiram (e.g., 0.00 μM, 0.02 μM, 0.10 μM, 0.33 μM, 1.65 μM, 6.25 μM, and 25.02 μM).

Cytokine levels in the cellular supernatant were evaluated using the FirePlex-HT assay system with the Human Cytokines FirePlex-HT Panel 1 (ab234897; Abcam). Morphological/cellular phenotypes were assayed.

Disulfiram demonstrated notable effects on cellular phenotypes in older immune cells that were suggestive of a rejuvenation of the response to infection.

Disulfiram significantly reduced several proinflammatory cytokines when compared with old untreated controls. MCP1, IL-1β, IL-6, and TNFα all significantly decreased in at least 2 doses (FIG. 1A). Again, the reduction in MCP1 followed a downward dose response (0.02 μM [P=0.35]; 0.1 μM [P=0.04]; 0.33 μM [P<0.001]; 1.65 μM [P<0.001]; 6.25 μM [P<0.001]; 25.02 μM [P<0.001]; FIG. 1A). IL-1β was significantly reduced after the second lowest dose, then stayed significantly low for all higher doses (0.02 μM [P=0.28]; 0.1 μM [P=0.005]; 0.33 μM [P=0.001]; 1.65 μM [P=0.004]; 6.25 μM [P=0.004]; 25.02 μM [P<0.001]; FIG. 1A). These anti-inflammatory effects caused disulfiram showing its potential to improve older viral immune responses to infection.

Disulfiram improved the appearance of virally infected cells. Untreated and treated PBMCs were exposed to 10×MOI rVSV, yet, at several doses, disulfiram made the cells appear like they were responding to a lower viral load. Compared with old controls, which appeared to be responding to 10×MOI rVSV, the higher doses of disulfiram made the cells appear to be responding to a lower viral load (0.02 μM [P=0.63]; 0.1 μM [P=0.01]; 0.33 μM [P=0.43]; 1.65 μM [P=0.05]; 6.25 μM [P<0.001]; 25.02 μM [P<0.001]). The higher doses of disulfiram also significantly reduced the percentage of the mitochondria with a reticular shape (0.02 μM [P=0.04]; 0.1 μM [P=0.42]; 0.33 μM [P<0.001]; 1.65 μM [P<0.001]; 6.25 μM [P<0.001]; 25.02 μM [P<0.001]; FIG. 1B). Both of these effects restore important phenotypes of the older viral immune response.

T cells treated with disulfiram also exhibited a much younger phenotype compared with old untreated controls. The first two doses of disulfiram saw a significant rejuvenating effect on the T-cell age scores in the multi-phenotype aging profiles (0.02 μM [P<0.001]; 0.1 μM [P=0.005]; FIG. 1C). The higher doses of disulfiram also saw significant, beneficial reductions in the T-cell age score (0.33 μM [P<0.001]; 1.65 μM [P<0.001]; 6.25 μM [P<0.001]; 25.02 μM [P<0.001]; FIG. 1C).

Similar trends were seen with the “on-age” and “off-age” scores. Compared with controls, the “on-age” T-cell score significantly shifted in the young direction after treatment with disulfiram (0.02 μM [P=0.003]; 0.1 μM [P=0.11]; 0.33 μM [P<0.001]; 1.65 μM [P<0.001]; 6.25 M [P<0.001]; 25.02 μM [P<0.001]; FIG. 1D). The “off-age” score also had a significant effect but only in the higher doses (0.02 μM [P=0.26]; 0.1 μM [P=0.44]; 0.33 μM [P<0.001]; 1.65 μM [P=0.008]; 6.25 μM [P=0.003]; 25.02 μM [P=0.01]; FIG. 1D). All these beneficial shifts in age-related phenotypes show the strong beneficial potential of disulfiram for treating dysfunction in the older viral immune response.

Machine learning model predictions of the immune response resulting from different viral loads (at 0.1×, 1×, and 10×MOI) were notably different with disulfiram treatment compared with untreated control cells. At higher disulfiram concentrations, the model indicated that monocytes responded at a lower MOI than did untreated control cells.

Together, disulfiram restored multiple aspects of the viral immune response of older adults to a younger state demonstrating its usefulness in therapeutic methods of the present disclosure.

Disulfiram also appeared to operate via several anti-inflammatory mechanisms, including an ability to inhibit NLRP3 inflammasome-mediated pyroptotic cell death. The inflammasome-blocking mechanisms of disulfiram ultimately inhibits pyroptosis by stopping formation of pores in the cell membrane that lead to cell lysis and release of proinflammatory molecules such as IL-1β and IL-18. The data presented herein show that disulfiram restores aspects of the old viral immune response.

These data demonstrated significant anti-inflammatory and rejuvenating effects by disulfiram. Disulfiram reduced the proinflammatory cytokines MCP1, IL-1β, IL-6, and TNFα while also rejuvenating several other features in aging profile such as T-cell age score, viral load response, and mitochondrial function. These immunomodulatory mechanisms could be related to the ability of disulfiram to block the final step in inflammasome-mediated pyroptosis and cytokine release. Disulfiram may also operate by ultimately reducing pore formation on the cell membrane of neutrophils, which would allow for the release of neutrophil extracellular traps (NETs), a process known as NETosis. Both of these mechanisms make disulfiram an attractive treatment for hyperinflammatory infections such as COVID-19 and sepsis. Disulfiram has already been shown to protect mice from lethal lipopolysaccharide-induced septic shock. By targeting any of these mechanisms, disulfiram may be a useful agent for treating infection, e.g., caused by a virus such as SARS-CoV2.

Sera from patients with severe COVID-19 demonstrated increased NETs and an autopsy of a lung specimen from a patient with COVID-19 showed extensive neutrophil infiltration. Proinflammatory cytokines in patients with severe COVID-19 were significantly higher than in moderate cases. This includes elevated levels of IL-1β that result from inflammasome activation. Given the relationship between NETosis, the inflammasome, and COVID-19 pathology, the ability of disulfiram to target these pathways, treatments with disulfiram could provide substantial clinical benefit.

In addition to improving host response, disulfiram may have antiviral effects on SARS-CoV2. Disulfiram has been shown to inhibit papain-like proteases of deadly coronaviruses such as Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV, which may disrupt the replication and IFN suppression mechanisms of these viruses. This experiment is performed by contacting the virus-infected cells with different concentrations of disulfiram in combination of cinnamaldehyde. Cell parameters such as cytokine levels and morphological/cellular phenotypes are assayed to demonstrate potential to improve old immune response to infection.

Example 3: Synergistic Effect of Disulfiram and Cinnamaldehyde

A luciferase assay was performed as described briefly: 125 k THP1 pyroptosis reporter cells/ml final density were plated on 384 well plates and incubated with disulfiram, cinnamaldehyde, or disulfiram and cinnamaldehyde for 20 minutes. 1 μg/ml LPS was added to the wells, and the plate was incubated for 3 hours, followed by addition of 10 μM nigericin. After three hours, supernatants were harvested and the presence of HMGB1 luciferase reporter protein was quantified using QUANTI-Luc.

FIG. 2 shows the effect on pyroptosis of the combination of disulfiram and cinnamaldehyde as compared to each individual compound. FIG. 3 shows the potentiating effects of varying constant concentrations of cinnamaldehyde added to disulfiram titration curves.

Inhibition of pyroptosis was assessed by inducing inflammasome activation in THP1 HMGB1 Lucia cells (Invivogen). These cells code for a luciferase reporter protein (HMGB1) that is released from cells during pyroptosis. HMGB1 levels in the supernatant can therefore be used to quantify pyroptosis.

Concentration matrices of disulfiram titration curves mixed with titration curves of cinnamaldehyde were tested. Disulfiram curves at each concentration of cinnamaldehyde were plotted and fit using a log(agonist) vs. response variable slope (four parameters) least squares fit model. The diagonal of each matrix was representative of a dose response curve of disulfiram plus cinnamaldehyde combinations titrated at a constant ratio.

Synergy Assessment of Disulfiram Combinations

Synergy fold ratio was measured by calculating the ratio of actual effect over expected effect: [(cinnamaldehyde+disulfiram)/no treatment]/[(disulfiram alone/no treatment)×(cinnamaldehyde alone/no treatment)] at each concentration combination. Values greater than 1 were considered synergistic.

Synergy using the Loewe additivity model was calculated using synergyfinder package on R (software environment for statistical computing and graphics; see the World Wide Web (at) /bioconductor.org/packages/release/bioc/vignettes/synergyfinder/inst/doc/synergyfinder.pdf, the contents of which is incorporated by reference in its entirety). The Loewe additivity model assumes the null hypothesis that a combination of drugs is the same as increasing the concentration of either drug alone (i.e. the effect is simply additive rather than the drugs interacting to produce a greater effect).

-   -   y_(e) is the effect as if a drug is combined with itself, i.e.,         y^(e)=y₁(x₁+x₂)=y₂(x₁+x₂).

Using R, the synergy score is calculated using ye, and determined to be the difference between the observed effect and the expected effect. Score negativity or positivity determines whether the combination is synergistic or antagonist, respectively. Loewe S. (1953), The problem of synergism and antagonism of combined drugs. Arzneimittelforschung 3, 285-290; Loewe, S. (1928). Die quantitativen probleme der pharmakologie. Ergebnisse Physiol. 27, 47-187, the contents of which is incorporated by referenced in its entirety.

FIG. 4A to 4C show the synergistic effect of the combination of disulfiram and cinnamaldehyde mediated inhibition of pyroptosis.

IC50 Calculations

IC50s were calculated using the log(agonist) vs. response variable slope (four parameters) least squares fit model from the GraphPad Prism software package.

The percent difference between disulfiram alone and each disulfiram+cinnamaldehyde curve was calculated, and two replicates for each condition were averaged. Statistical significance was determined using a standard Student's t-test (unpaired, 2-tailed).

Individual curves for disulfiram alone, cinnamaldehyde alone, and the combination of the two were plotted as log of the relative concentrations of each. In these experiments, disulfiram and cinnamaldehyde were titrated equally with different starting concentrations of disulfiram and cinnamaldehyde and so the relative ratio of disulfiram:cinnamaldehyde was maintained across the entire curve. The concentrations were normalized so that 1 is set as the median for each curve, and the curves are plotted as 1.5× dilution series.

Curves of disulfiram+constant concentrations of cinnamaldehyde were plotted using the log of disulfiram concentration.

FIG. 5 is a table showing the percent leftward shift in IC50 mediated by cinnamaldehyde relative to disulfiram alone in a dose-dependent matter, while cinnamaldehyde alone has no effect on pyroptosis inhibition or IC50. Accordingly, these data show synergistic effects on pyroptotic inhibition when cells are subjected to a combination of disulfiram and cinnamaldehyde.

Example 4: Methods that Comprise Administering Disulfiram and Cinnamaldehyde

In this example, a composition comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde are administered to a mammal, e.g., a human, for increasing lifespan, for preventing or treating a disease including an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system (e.g., for treating an infection).

The dose of disulfiram is from about 5 mg to about 500 mg. The dose of the cinnamaldehyde is from about 0.001 mg to about 223 mg.

Administration of the compositions is by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered. Alternately, the compositions are administered orally, by inhalation, or topically. Combinations of administration routes may be used.

The mammal's lifespan is measured and the presence, absence, and/or severity of various aging-related disorders are determined; these are compared to control mammals and/or to historical controls to determine the effectiveness of the composition administered.

The mammal may be aged or not aged.

The mammal may have a healthy immune system or the mammal may have an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.

Illustrative diseases treated in this example may be asthma, deafness, or a viral infections and an illustrative symptom thereof may be sepsis.

Assays and formulations used in this example are related to those described in US20190228840, the entire contents of which is incorporated by reference its entirety.

Example 5: Methods for Preventing and/or Treating a Respiratory Disease or Disorder

In this example, a composition comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde are administered to a mammal, e.g., a human, for preventing and/or treating a respiratory disease or disorder, e.g., acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS).

The dose of disulfiram is from about 5 mg to about 500 mg. The dose of the cinnamaldehyde is from about 0.001 mg to about 223 mg.

Administration of the compositions is by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered. Alternately, the compositions are administered orally, by inhalation, or topically. Combinations of administration routes may be used.

Treatment is identified as an improvement in the administered mammal in one or more of the following symptoms severe shortness of breath, labored and unusually rapid breathing, low blood pressure, and confusion and extreme tiredness. The improvement may be relative to the pre-administration state for the mammal.

The mammal may be aged or not aged.

The underlying cause for the ALI and/or ARDS may be sepsis (e.g., a serious and widespread infection of the bloodstream); inhalation of a harmful substance (e.g., smoke, chemical fumes, asbestos, dust, particulates, vomit, and water); viral or bacterial pneumonia (which may affect up to all five lobes of the lungs) and other respiratory disorders including those caused by a coronavirus (e.g., SARS, MERS, and COVID-19), influenzas (influenza A, influenza B, or parainfluenza), pneumococcal infection, adenovirus, respiratory syncytial virus (RSV), enterovirus and/or other respiratory viral infections; and a head, chest or other major injury; or another cause (e.g., pancreatitis which is inflammation of the pancreas, a massive blood transfusion, and severe burns).

In some embodiments, ALI differs from ARDS in that ALI exists during early stage of a respiratory disease and ARDS exists during a later state of the respiratory disease.

In some embodiments, the composition or compositions prevent or treat idiopathic pulmonary fibrosis and/or chronic obstructive pulmonary disease.

Example 6: Methods for Improving a Vaccine Response

In this example, a composition comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde are administered to a mammal, e.g., a human, for improving effectiveness of a vaccine that is administered to the mammal.

The dose of disulfiram is from about 5 mg to about 500 mg. The dose of the cinnamaldehyde is from about 0.001 mg to about 223 mg.

The compositions may be administered by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered. Alternately, the composition may be administered orally, by inhalation, or topically. Combinations of administration routes may be used.

Administration of the vaccine may be by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered. Alternately, the vaccine may be administered orally, by inhalation, or topically.

In some cases, the composition(s) comprising the combination of disulfiram and/or cinnamaldehyde and the vaccine are administered contemporaneously. In other cases, the vaccine is administered subsequent to the administration of the combination(s) of disulfiram and/or one or more additional ingredients. In some cases, the vaccine is administered before the administration of the combination(s) of disulfiram and/or cinnamaldehyde. A subject may be administered vaccines and/or combination(s) of disulfiram and/or one cinnamaldehyde multiple times and in any order.

The vaccine may be a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human immunodeficiency virus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (part of the DTaP combined vaccine) vaccine, or Yellow fever vaccine. In embodiments, the vaccine is a coronavirus vaccine. In embodiments, the coronavirus vaccine is directed against Sars-CoV-2.

The mammal may be aged or not aged.

The mammal may have a healthy immune system or the mammal may have an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.

The mammal's ability to fend off a subsequent infection is determined and compared to mammals and/or historical controls who were only administered the vaccine.

The mammal's ability to later produce antibodies directed to an infectious agent (related to the vaccine) is determined and compared to mammals and/or historical controls who were only administered the vaccine.

Example 7: Methods for Treating Skin Disorders

In this example, a composition comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde are administered to a mammal, e.g., a human, for treating a skin disorder.

The dose of disulfiram is from about 5 mg to about 500 mg. The dose of the cinnamaldehyde is from about 0.001 mg to about 223 mg.

The compositions may be administered orally or topically, with a dose depending on the quantity of composition needing to be administered. The compositions may be formulated as a gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, or aerosol or administered via an impregnated solid support (e.g., a patch)). Alternately, the composition may be administered by injection or by inhalation. The composition(s) may be administered orally. Combinations of administration routes may be used.

The mammal has a skin disorder, e.g., wrinkles, which may be a result of photoaging or related to actinic keratosis. Other skin disorders the mammal may have includes dermal atrophy (thinning of the skin), lentigines (aging spots), vaginal atrophy, prolonged/inefficient wound healing, and/or xerosis cutis (skin dryness). In examples, the mammal has moderate skin aging (i.e., Glogau Classification III).

The composition's or compositions' ability to treat a skin disorder, e.g., wrinkles, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions. For example, the determination relates to a change in the Glogau Classification.

Example 8: Methods for Treating Dry Eye

In this example, a composition comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde are administered to a mammal for improving treating dry eye.

The dose of disulfiram is from about 5 mg to about 500 mg. The dose of the cinnamaldehyde is from about 0.001 mg to about 223 mg.

The compositions may be administered topically, with a dose depending on the quantity of composition needing to be administered. The compositions may be formulated as eye drops or as eye ointments.

The composition's or compositions' ability to treat dry eyes, is determined and compared to mammal before administration and/or to historical controls who were not administered the composition or compositions.

Example 9: Methods for Treating Alopecia

In this example, a composition comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde are administered to a mammal, e.g., a human, for treating alopecia.

The dose of disulfiram is from about 5 mg to about 500 mg. The dose of the cinnamaldehyde is from about 0.001 mg to about 223 mg.

The compositions may be administered topically, with a dose depending on the quantity of composition needing to be administered. The compositions may be formulated as a gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, or aerosol or administered via an impregnated solid support (e.g., a patch)). Alternately, the composition may be administered by injection or by inhalation. The composition(s) may be administered orally. Combinations of administration routes may be used.

The composition's or compositions' ability to treat alopecia, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions.

Example 10: Methods for Treating a Skin Cancer

In this example, a composition comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde are administered to a mammal, e.g., a human, for treating a skin cancer, e.g., (e.g., basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)).

The dose of disulfiram is from about 5 mg to about 500 mg. The dose of the cinnamaldehyde is from about 0.001 mg to about 223 mg.

The compositions may be administered topically, with a dose depending on the quantity of composition needing to be administered. The compositions may be formulated as a gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, or aerosol or administered via an impregnated solid support (e.g., a patch)). Alternately, the composition may be administered by injection or by inhalation. The composition(s) may be administered orally. Combinations of administration routes may be used.

The composition's or compositions' ability to treat the skin cancer, e.g., BCC and SCC, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions.

Example 11: Methods that Comprise Administering a First Composition and a Second Composition

In this example, a first composition comprises a therapeutically effective amount of disulfiram and a second composition comprising cinnamaldehyde are administered to a mammal for increasing lifespan, for preventing or treating a disease including an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system.

The dose of disulfiram is from about 5 mg to about 500 mg. The dose of the cinnamaldehyde is from about 0.001 mg to about 223 mg.

The first composition is administered orally, by inhalation, injection, or topically. The second composition is administered orally, by inhalation, injection, or topically. The administration route of the first composition and the second composition may be the same or may be different.

The first composition may be administered before the second composition is administered.

The first composition may be administered after the second composition is administered.

The first composition and the second composition may be administered contemporaneously (either by combining the two compositions or by administering the two compositions at nearly the same time).

The mammal's lifespan is measured and the presence, absence, and/or severity of various aging-related disorders are determined; these are compared to control mammals and/or to historical controls to determine the effectiveness of the first composition administered. 

What is claimed is:
 1. A method for inhibiting and/or reducing pyroptotic cell death in a cell, the method comprising contacting the cell with an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde, thereby inhibiting and/or reducing pyroptotic cell death, wherein the amount of disulfiram is from about 5 mg to about 500 mg and the amount of cinnamaldehyde is from about 0.01% to about 45% by weight of disulfiram.
 2. The method of claim 1, wherein disulfiram and cinnamaldehyde are included in one composition and the composition consists essentially of disulfiram and cinnamaldehyde.
 3. The method of claim 1, wherein the method comprises contacting the cell with a first composition consisting essentially of disulfiram and contacting the cell with a second composition consisting essentially cinnamaldehyde.
 4. The method of claim 1, wherein inhibiting and/or reducing pyroptotic cell death in the cell increases the lifespan of the cell.
 5. The method of claim 1, wherein the cinnamaldehyde further potentiates disulfiram's ability to treat acute lung injury (ALI), acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, dry eye, actinic keratosis, alopecia, and/or skin a cancer.
 6. The method of claim 1, wherein the cinnamaldehyde further potentiates disulfiram's ability to inhibit and/or reduce a pathological inflammatory response, alter a T-cell's age, and/or alter mitochondrial function in the cell.
 7. A method for boosting activity of an immune cell, the method comprising contacting the immune cell with an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde, thereby boosting activity of the immune cell, wherein the amount of disulfiram is from about 5 mg to about 500 mg and the amount of cinnamaldehyde is from about 0.01% to about 45% by weight of disulfiram.
 8. The method of claim 7, wherein disulfiram and cinnamaldehyde are included in one composition and the composition consists essentially of disulfiram and cinnamaldehyde.
 9. The method of claim 7, wherein the method comprises contacting the cell with a first composition consisting essentially of disulfiram and contacting the immune cell with an at least second composition consisting essentially cinnamaldehyde.
 10. The method of claim 7, wherein boosting activity of the immune cell increases an effective immune response against an infectious agent and/or an atypical cell.
 11. The method of claim 7, wherein boosting activity of the immune cell improves the immune cell's response against a component contained in a vaccine, wherein the component contained in the vaccine is an antigen obtained from, related to, homologous to, or expressed by an infectious agent.
 12. The method of claim 7, wherein boosting activity of the immune cell comprises inhibiting a pathological immune response.
 13. The method of claim 12, wherein boosting activity of the immune cell minimizes overactive immune cell activity. 